Skip to main content
NCBI home page
Frontiers in Epigenetics and Epigenomics logoLink to Frontiers in Epigenetics and Epigenomics
. 2026 Jan 20;3:1733711. doi: 10.3389/freae.2025.1733711

Professor Emma Whitelaw, a pioneer of epigenetic inheritance

Alyson Ashe 1,*, Jessica J Hawes 1
PMCID: PMC13639316  PMID: 42840274

Abstract

Here we explore the contribution of Professor Emma Whitelaw to the fields of epigenetics and transgenerational epigenetic inheritance. We highlight some recent advances to the field, while integrating the work of Professor Whitelaw and her team within our current understanding of epigenetic mechanisms.

Keywords: ENU mouse mutagenesis, epiallele, epigenetics (chromatin remodeling), epigenetics (DNA methylation), genetic screen

In 1942, Conrad Waddington coined the term ‘Epigenetics’ to describe the “complex of developmental processes” that bridge the genotype and phenotype (Waddington, 1942). Waddington was, first and foremost, a developmental biologist interested in the complexities of development that are recapitulated with remarkable robustness in every individual. Today, the most commonly accepted definition of epigenetics is ‘the study of changes in gene expression that do not involve alterations of the underlying DNA sequence’. However, some argue that epigenetics should only refer to cellular memory and reprogramming (Greally, 2018), while others take a much broader view of epigenetic mechanisms and their implications for a developing organism and its offspring, such as epigenetic inheritance (for conflicting opinions, see (Deichmann, 2020; Jablonka, 2017)).

While the definition of epigenetics itself is debated, so too is the precise nature of what encompasses epigenetics at a molecular level. Historically, only methylation and other post-translational modifications of DNA and the histone proteins around which it wraps were considered epigenetics (Felsenfeld, 2014). Others consider non-coding RNAs that can post- or co-transcriptionally silence genes and transcription factors to also be epigenetic factors (Mangiavacchi et al., 2023). More recently, mechanisms that regulate gene expression through the spatial and structural arrangement of chromatin in the nucleus have also been brought under the umbrella of epigenetics, such as chromatin looping, the tethering of loci together to facilitate transmission of chromatin state, and DNA supercoiling (Cavalli and Misteli, 2013; Gilbert and Marenduzzo, 2025).

Epigenetic inheritance is the idea that epigenetic signals may be passed between generations, from parent to offspring, where they can have a functional consequence in offspring. Such inheritance can be either intergenerational or transgenerational and is highly controversial. Epigenetic inheritance goes against the strict definition of Neo-Darwinism, which is the theory that evolution proceeds solely through natural selection on random mutations alone. However, attractive as the idea may be for some, there are many barriers to widespread acceptance of epigenetic inheritance. These barriers are both biological (for example, the Weismann barrier (Weismann, 1893)) and intellectual (for example, the perceived alignment between epigenetic inheritance and Lamarck’s theory of inheritance of acquired traits. For detailed reviews, see (Bird, 2024; Deichmann, 2016; Heard and Martienssen, 2014; Miska and Ferguson-Smith, 2016; Perez and Lehner, 2019)).

In this perspective, we will set aside the complexities and controversies that plague the field, and focus on one of the pioneers of mammalian epigenetic inheritance, Prof. Emma Whitelaw (who retired in the mid 2010s). Whitelaw was driven to epigenetics, like Waddington, from a developmental perspective. Specifically, she studied the regulation of globin genes in mice (Whitelaw et al., 1989). Having learnt mouse transgenesis on the weekends from her friend Rosa Beddington (a talented developmental biologist and embryologist whose life was tragically cut short in 2001 (Rastan and Robertson, 2001)), Whitelaw developed independent lines (each with a unique integration site) of transgenic mice carrying a globin gene promoter driving beta-galactosidase expression in mouse erythrocytes. She found that these lines of mice each displayed variable percentages of erythrocytes that expressed beta-galactosidase, but that this variegation was highly consistent within a line (Robertson et al., 1995), a phenomenon strikingly similar to position-effect variegation (PEV) in the eyes of Drosophila (Reuter and Spierer, 1992). Furthermore, she showed that this stochastic expression appeared to be driven by the integration site and by chromatin accessibility, but not DNA methylation (Garrick et al., 1996).

Intrigued by the stochastic nature of the silencing she observed in the erythrocytes, she began working on the agouti viable yellow (Avy) strain of mice. These mice have coats that vary between individuals from completely yellow to completely agouti, with a full spectrum of variegation in between. This mouse line was molecularly characterized by others (Duhl et al., 1994; Wolff et al., 1998) but Whitelaw and her team noticed that the spectrum of yellow colouration in the coats of offspring was, in part, heritable and dependent on the phenotype of the mother and grandmother (Morgan et al., 1999). A series of elegant experiments confirmed that this effect was not due to the uterine environment or an effect on the oocytes before fertilisation, suggesting that an epigenetic signal was being inherited from one generation to the next (and the next). Furthermore, they showed that the degree of yellow in the coat correlated with DNA methylation at an intracisternal-A particle (IAP) retrovirus inserted just upstream of the agouti gene. Subsequent experiments suggested that this DNA methylation could not be the sole cause of the epigenetic inheritance, as blastocysts from both yellow and pseudoagouti mothers displayed complete erasure of DNA methylation at the agouti locus (Blewitt et al., 2006). The Avy mice were the first example of epigenetic inheritance in mammals and have served as the poster child for the field ever since, with pictures of mice with differing coat colours being incorporated in many undergraduate lectures and conference presentations on epigenetics.

Shortly after this paper, Whitelaw and her team published two more papers identifying more instances of epigenetic inheritance and parental effects in mice (at the Axin Fu allele, and once again in erythrocytes, this time with a GFP reporter (Preis et al., 2003; Rakyan et al., 2003)). Similarly to the A vy allele, they showed that the Axin Fu allele was associated with variable methylation at an IAP (intracisternal A-particle) element, in this case inserted into intron 6 of the axin gene (Rakyan et al., 2003). They coined the term metastable epialleles to describe such loci of variable penetrance (Rakyan et al., 2002) in which the epigenetic landscape at a given sequence varies between individuals, but is consistent across the tissues of an individual, somewhat like an epigenetic fingerprint. It is worth nothing that subsequent work by the lab of Anne Ferguson-Smith has shown that A vy and Axin Fu are not the norm: although a subset of IAP elements display variable methylation patterns, and an even smaller subset display low penetrance of epigenetic inheritance, most display robust reprogramming of their methylation between generations (Elmer et al., 2021; Kazachenka et al., 2018). Similar results were also found recently by the Waterland lab in a genome-wide screen for metastable epialleles (Gunasekara et al., 2025).

Driven by a desire to understand more about the underlying biology of these puzzling phenomena and inspired by similar screens for modifiers of PEV in Drosophila and paramutation in maize that showed genetic control of epigenetic phenomena (Hollick and Chandler, 2001; Schotta et al., 2003), Whitelaw and her team embarked on a set of ambitious ENU mutagenesis screens (the Momme screens, meaning Modifiers of murine metastable epialleles) (Ashe et al., 2008; Blewitt et al., 2005; Daxinger et al., 2012; Daxinger et al., 2013). The first Momme screen was performed when large-scale ENU mutagenesis screens had only recently been developed in mice (de Angelis et al., 2000; Nolan et al., 2000; Soewarto et al., 2000) and took advantage of a variegating erythrocyte GFP reporter mouse line (Preis et al., 2003). Crucially, this enabled relatively fast and simple FACS-based screening of potential mutants. The goal of these ENU screens was to discover the genes controlling epigenetic regulation of gene expression, with the hypothesis that many of these genes would have fundamentally important roles in epigenetic control of development, and potentially epigenetic inheritance. And indeed, this is what they found.

Although the ENU mutagenesis screens were performed on a transgene expressed in erythrocytes, the mutations discovered spanned the breadth of what are now characterised as epigenetic processes (Figure 1; Table 1). It is unsurprising, given what we currently know about gene silencing, that DNA methyltransferases were amongst the Momme mutants (Ashe et al., 2008; Whitelaw et al., 2010; Youngson et al., 2013). Indeed, MommeD2, the second Momme line to be isolated, was shown in 2007 to contain a probable loss-of-function allele of Dnmt1 (Chong et al., 2007). Although the methylation status at the GFP transgene was not characterised, Dnmt1 MommeD2/+ mice showed an increased proportion of yellow offspring when crossed to the A vy mouse line, consistent with a loss of silencing resulting from less DNA methylation at the locus (Blewitt et al., 2005; Chong et al., 2007).

FIGURE 1.

Network diagram illustrating interactions among proteins identified in the Mommes screen. Colored nodes represent proteins, and connecting lines represent predicted and known interactions. Proteins are grouped into clusters based on their roles in DNA methylation, histone methylation, erythrocyte development, and chromatin remodeling, or as transcription factors. Each cluster is labelled, showing interconnectedness among candidates identified in the screen.

Open in a new tab

A string network of the identified hits from the Momme screens. Nodes represent proteins and are clustered and colored based on known function or activity. The darkness of the lines between nodes indicates the confidence of the associations (darker line indicates higher confidence). Associations do not necessarily indicate physical binding, but rather a shared or similar function. Generated using the STRING database (Szklarczyk et al., 2023).

TABLE 1.

A summary of the genes found in the ENU mutagenesis screens performed by the Whitelaw Lab. D refers to genes found in dominant screens and R to those found in recessive screens. The table includes only those lines that have currently been mapped, and not those that remain unknown.

Momme mutant Gene Protein function References for momme mutant(s)
D10, D16 Baz1b Tyrosine-protein kinase BAZ1B. Component of chromatin remodelling complex (Oppikofer et al., 2017) Ashe et al. (2008), Daxinger et al. (2013)
D42 Brd1 Bromodomain-containing protein 1. Interacts with histone acetyltransferases and methyltransferases (Mishima et al., 2011) Daxinger et al. (2013)
D2, D32 Dnmt1 DNA methyltransferase 1. Maintains CpG methylation over DNA replication Chong et al. (2007), Daxinger et al. (2013)
D14 Dnmt3b DNA methyltransferase 3b. Involved in establishing CpG methylation de novo Youngson et al. (2013)
D12, D38 eIF3h Component of EIF3 complex. Required for the initiation of protein synthesis (Masutani et al., 2007) Daxinger et al. (2012)
D6, D20 Fam208a TASOR. Component of HUSH complex, involved in silencing retrotransposons (Douse et al., 2020) Harten et al. (2014)
D7 Hbb-b1 Hemoglobin subunit beta-1. Involved in oxygen transport Brown et al. (2013)
D5 Hdac1 Histone deacetylase 1. Component of multiple chromatin modifying and remodelling complexes, such as NuRD (nucleosome remodelling complex) Ashe et al. (2008), Blewitt et al. (2005)
D11, D45 Klf1 Krueppel-like factor 1. Transcriptional regulator for beta-globin gene promoter Sorolla et al. (2015)
D41 Morc3 MORC family CW-type zinc finger protein 3, binds H3K4me0/1/2/3 and has ATPase activity which facilitates phase separation (Zhang et al., 2019) Desai et al. (2021)
D46 Nrf1 Nuclear respiratory factor 1. CNC-bZIP transcription factor essential for development and maintenance of homeostasis, involved in DNA hypomethylation Sorolla et al. (2021)
D27 Pbrm1 Protein polybromo-1. Component of PBAF SWI/SNF chromatin remodelling complex (Hao et al., 2025) Daxinger et al. (2013)
D18 Rif1 Rap-interacting factor 1. Involved in DNA damage response to promote repair of double-strand breaks (Kumar and Cheok, 2014) Daxinger et al. (2013)
D8, D26, D28, D34 Rlf Rearranged L-myc fusion. Necessary for DNA hypomethylation at specific loci, likely involved in development through NOTCH signalling (Bourke et al., 2017) Daxinger et al. (2013)
D13, D17 Setdb1 Histone-lysine N-methyltransferase SETDB1. Methylates H3K9, especially at repetitive elements and developmental genes (Padeken et al., 2022) Daxinger et al. (2013)
D39 Smarca4 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4. ATPase subunit of SWI/SNF chromatin remodelling complex (Ahmad et al., 2024) Daxinger et al. (2013)
D4, D35, D37 Smarca5 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5. ATPase component of imitation switch (ISWI) chromatin remodelling complex (Goodwin and Picketts, 2018) Blewitt et al. (2005), Chong et al. (2007), Daxinger et al. (2013)
D19 Smarcc1 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily c, member 1. Component of BAF complex from SWI/SNF family of chromatin remodellers (Ahmad et al., 2024) Daxinger et al. (2013)
D1, D23, D36, D43 Smchd1 Structural maintenance of chromosomes flexible hinge domain-containing protein 1. Epigenetic repressor involved in X-chromosome inactivation (Huang et al., 2025) Blewitt et al. (2005), Blewitt et al. (2008), Daxinger et al. (2013), Tapia del Fierro et al. (2023)
D33 Suv39h1 Histone-lysine N-methyltransferase Suppressor of variegation 3-9 homolog 1. Histone methyltransferase involved in H3K9 methylation to establish pericentric heterochromatin and de novo gene silencing (Padeken et al., 2022) Daxinger et al. (2013)
D9, D31 Trim28 Tripartite motif protein 28. E3 ubiquitin protein ligase, involved in formation of chromosome loops, can recruit chromatin remodelling complexes and histone modifiers (Czerwińska et al., 2017; Wei et al., 2025) Daxinger et al. (2013), N. C. Whitelaw et al. (2010)
D44 Trim33 Tripartite motif protein 33/TIF1γ. E3 ubiquitin protein ligase, can promote transcriptional elongation and DNA damage repair (He et al., 2006; Yu et al., 2019) Isbel et al. (2015)
D40 Uhrf1 Ubiquitin-like with PHD and RING finger domains 1. Maintains DNA methylation through interactions with DNMT1, can bind methylated DNA and histone H3K9me2/3 (Ferry et al., 2017) Daxinger et al. (2013)
D30 Wiz Widely interspaced zinc finger-containing protein. Involved in heterochromatin formation through recruitment of histone methyltransferases, associates with DNA loop anchors alongside CTCF and Cohesin (Justice et al., 2020) Daxinger et al. (2013), Isbel et al. (2016)
R1 Foxo3a Forkhead box protein O3. ‘Winged helix’ or ‘Forkhead’ transcription factor, regulates development and cell-cycle control (Cao et al., 2023) Youngson et al. (2011)
R2 Uba2 SUMO-activating enzyme subunit 2. Mediates ATP-dependent activation of SUMO proteins necessary for genome stability, nuclear organisation and maintaining repressive chromatin states (Poleshko et al., 2014) Ashe (2007)
Open in a new tab

Other mutants were more enigmatic at the time of discovery, and some remain mysterious. For example, numerous chromatin writers, readers and remodellers were hit (Ashe et al., 2008; Blewitt et al., 2005) when the ‘histone code’ theory had only recently been proposed (Strahl and Allis, 2000). For example, MommeD10 mutant mice were shown to have a mutation in Williams syndrome transcription factor/Baz1b. DNA methylation at the transgene locus was not altered in MommD10 +/− or MommeD10 −/− mice, and so the hypothesis was made that changes to transgene expression were caused by alterations at the chromatin level (Ashe et al., 2008). BAZ1B encodes a protein containing a bromodomain and PHD finger, two domains commonly associated with chromatin binding, and is a subunit of the SMARCA5 chromatin remodelling complex (Oppikofer et al., 2017). It also plays an important role in DNA repair (Aydin et al., 2014; Kim et al., 2024), and heterochromatin replication (Bozhenok, 2002; Goto et al., 2024), although at the time of its discovery as MommeD10, most of this was not known. Importantly, MommeD10 −/− mice showed craniofacial abnormalities reminiscent of humans with Williams-Beuren syndrome, and this was consistent with its expression pattern in mouse embryos, suggestive of a causative role for BAZ1B in this syndrome (Ashe et al., 2008).

Another of the first Mommes, MommeD1, was discovered to have a mutation in a previously uncharacterised gene, Structural maintenance of chromosomes hinge domain 1 (Smchd1) and was shown to be critical for X-inactivation (Blewitt et al., 2008). This discovery led to a plethora of research defining the role of Smchd1 not only in X inactivation, but also facioscapulohumeral muscular dystrophy and bosma arrhinia microphthalmia syndrome (reviewed in (Gurzau et al., 2020; Schall et al., 2019)) and most recently in heterochromatin maintenance more broadly (Huang et al., 2025). Yet another gene discovered in the Momme screen (MommeD8, D28 and D34), and not studied previously, rearranged L-Myc fusion (Rlf), helps to regulate DNA methylation levels at CpG islands (Harten et al., 2015), and its loss leads to developmental defects in the heart (Bourke et al., 2017). These Momme mutants (D1, D10, D8) collectively serve as examples of how the mutagenesis screen led directly to subsequent advances in our understanding of the role of epigenetic modifiers in development, in ways that could not have been predicted at the outset of the screen.

Many of the hits are involved not only in epigenetic regulation during development, but also current and emerging mechanisms of epigenetic inheritance. For example, TASOR (Fam208a), identified from the Momme screen more recently (Harten et al., 2014), is part of the HUSH complex which recruits SETDB1 (another Momme mutant (Daxinger et al., 2013)), to deposit H3K9me3 (Douse et al., 2020). Though H3K9me3 profiles were not studied in the initial Momme screens, we now know that DNA methylation and H3K9me3 work closely together and are both needed for effective and heritable silencing (Tatarakis et al., 2025). MORC3 is another Momme mutant (Desai et al., 2021) and has been identified as required for the recruitment of histone H3.3, a variant of H3, to maintain H3K9me3 and heterochromatic silencing at endogenous retroviruses (ERVs) (Groh et al., 2021). Very recently, the overexpression of H3.3 and its transport from somatic cells to the germline was observed in C. elegans as both a stimulus and potentiator of the transgenerational epigenetic inheritance of lysosomal lipolysis phenotypes (Zhang et al., 2025). These data highlight the regulation and trafficking of histone genes as emerging mechanisms of epigenetic regulation and inheritance.

TRIM28 is another interesting candidate from the screen, characterised as a bridge between histone deacetylases (via the NuRD complex), transcription factors, and histone methyltransferases (Czerwińska et al., 2017). Haploinsufficiency of Trim28 can trigger a bivalent epigenetic switch leading to obesity in a subset of mice within an isogenic population (Dalgaard et al., 2016; Whitelaw et al., 2010), and very recently, TRIM28 was linked to 3D genome organisation at chromosomal loops, necessary for the activation of CD8+ T-cells (Wei et al., 2025). TRIM33 is another tripartite motif containing protein identified in the Momme screen. It targets one of the youngest mouse retrotransposons in the germline, RLTR10B-containing LTRs, surveilling their activity (Isbel et al., 2015). TRIM28 and TRIM33 interact with TRIM27, a transcriptional regulator involved in early genome activation (Torres-Padilla and Zernicka-Goetz, 2006), to form a complex that can modulate hepatocellular carcinoma, one of the most common types of cancers worldwide (Herquel et al., 2011).

In the 15 years since Prof. Whitelaw and Dr Lucia Daxinger asserted that the study of transgenerational epigenetic inheritance had raised ‘more questions than answers’ (Daxinger and Whitelaw, 2010), have we made headway in finding solutions? The study of epigenetics has benefited from advancements in sequencing technologies, enabling lower input and higher accuracy in chromatin profiling, motif discovery, the introduction of spatial methods, and an ever-increasing library of protein and nucleic acid post-translational modifications (discussed in (Henikoff, 2023)). This has also facilitated precision epigenetic editing, such as through dCas9-fusions and TALEs (reviewed in (Roth et al., 2024)). Experiments using these editors and other thoughtfully engineered molecular tools have probed the heritability of epigenetic mechanisms in vivo, showing that marks such as DNA methylation, small RNAs and specific histone modifications can indeed be maintained across generations (Argaw-Denboba et al., 2024; Herridge et al., 2025; Takahashi et al., 2023).

It is widely accepted that transgenerational epigenetic inheritance can occur in invertebrates, such as C. elegans and D. melanogaster (reviewed in (Santilli and Boskovic, 2023)) and in plants (reviewed in (Cao and Chen, 2024)). The most prominent controversy still surrounds mammals (Bird, 2024). The epigenome appears, by nature, to be sensitive to subtle environmental perturbations, from social stress (Gapp et al., 2014; Weaver et al., 2004) to temperature (reviewed in (Murray et al., 2022)). Following molecular changes across generations is complicated by numerous confounders, including many we have yet to identify, making tracking inheritance difficult even in mouse models (Heard and Martienssen, 2014; Sapozhnikov and Szyf, 2024). In addition, negative results can be hard to publish, as pointed out by Whitelaw herself in 2015 (Whitelaw, 2015). Human studies are virtually impossible to perform in a properly controlled manner (Horsthemke, 2018), and studying transgenerational epigenetic inheritance requires multiple lifespans. Nonetheless, epidemiological studies on humans are suggestive of epigenetic inheritance (Kaati et al., 2007; Pembrey et al., 2006) and provide a context in which epigenetic inheritance could fit into adaptation, if one takes a broad view of epigenetic mechanisms (Jablonka, 2013).

Ultimately, as evidenced by the pioneering work of Prof. Emma Whitelaw and many of her peers, epigenetic mechanisms are multifaceted and complex. As we develop more sophisticated experimental tools, we are starting to see how some of the mutations from Whitelaw and colleagues’ mutagenesis screens could integrate into an architecture of epigenetic inheritance. Nonetheless, we believe epigenetics will remain an area where the questions consistently outnumber answers. Perhaps, as Whitelaw herself provocatively says, we even need new terminology: once we understand the molecular details of a phenomena, should it be classified as epigenetic anymore? (E. Whitelaw, pers. comm.).

Acknowledgements

The authors are extremely grateful to Emma Whitelaw for helpful discussions.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. JH was funded by the Australian Government Research Training Program (RTP) Scholarship.

Footnotes

Edited by: Steven Henikoff, Fred Hutchinson Cancer Center, United States

Reviewed by: Ute Deichmann, Ben-Gurion University of the Negev, Israel

Adrian Bird, University of Edinburgh, United Kingdom

Data availability statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

AA: Writing – review and editing, Writing – original draft, Conceptualization. JH: Writing – review and editing, Writing – original draft.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author AA declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

  1. Ahmad K., Brahma S., Henikoff S. (2024). Epigenetic pioneering by SWI/SNF family remodelers. Mol. Cell 84 (2), 194–201. 10.1016/j.molcel.2023.10.045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Argaw-Denboba A., Schmidt T. S. B., Di Giacomo M., Ranjan B., Devendran S., Mastrorilli E., et al. (2024). Paternal microbiome perturbations impact offspring fitness. Nature 629, 652–659. 10.1038/s41586-024-07336-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ashe A. (2007). Modifiers of epigenetic gene silencing. Sydney: University of Sydney. [Google Scholar]
  4. Ashe A., Morgan D. K. D. K., Whitelaw N. C. N. C., Bruxner T. J. T. J., Vickaryous N. K. N. K., Cox L. L. L., et al. (2008). A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biol. 9 (12), R182. 10.1186/gb-2008-9-12-r182 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Aydin Ö. Z., Marteijn J. A., Ribeiro-Silva C., Rodríguez López A., Wijgers N., Smeenk G., et al. (2014). Human ISWI complexes are targeted by SMARCA5 ATPase and SLIDE domains to help resolve lesion-stalled transcription. Nucleic Acids Res. 42 (13), 8473–8485. 10.1093/nar/gku565 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bird A. (2024). Transgenerational epigenetic inheritance: a critical perspective. Front. Epigenetics Epigenomics 2, 1434253. 10.3389/freae.2024.1434253 [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blewitt M. E., Vickaryous N. K., Hemley S. J., Ashe A., Bruxner T. J., Preis J. I., et al. (2005). An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc. Natl. Acad. Sci. U. S. A. 102 (21), 7629–7634. 10.1073/pnas.0409375102 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Blewitt M. E., Vickaryous N. K., Paldi A., Koseki H., Whitelaw E. (2006). Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2 (4), e49. 10.1371/journal.pgen.0020049 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Blewitt M. E., Gendrel A.-V., Pang Z., Sparrow D. B., Whitelaw N., Craig J. M., et al. (2008). SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat. Genet. 40 (5), 663–669. 10.1038/ng.142 [DOI] [PubMed] [Google Scholar]
  10. Bourke L. M., del Monte-Nieto G., Outhwaite J. E., Bharti V., Pollock P. M., Simmons D. G., et al. (2017). Loss of rearranged L-Myc fusion (RLF) results in defects in heart development in the mouse. Differentiation 94, 8–20. 10.1016/j.diff.2016.11.004 [DOI] [PubMed] [Google Scholar]
  11. Bozhenok L., Wade P. A., Varga-Weisz P. (2002). WSTF-ISWI chromatin remodeling complex targets heterochromatic replication foci. EMBO J. 21 (9), 2231–2241. 10.1093/emboj/21.9.2231 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brown F. C., Scott N., Rank G., Collinge J. E., Vadolas J., Vickaryous N., et al. (2013). ENU mutagenesis identifies the first mouse mutants reproducing human β-thalassemia at the genomic level. Blood Cells, Mol. Dis. 50 (2), 86–92. 10.1016/j.bcmd.2012.09.004 [DOI] [PubMed] [Google Scholar]
  13. Cao S., Chen Z. J. (2024). Transgenerational epigenetic inheritance during plant evolution and breeding. Trends Plant Sci. 29 (11), 1203–1223. 10.1016/j.tplants.2024.04.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cao G., Lin M., Gu W., Su Z., Duan Y., Song W., et al. (2023). The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. Life Sci. 328, 121877. 10.1016/j.lfs.2023.121877 [DOI] [PubMed] [Google Scholar]
  15. Cavalli G., Misteli T. (2013). Functional implications of genome topology. Nat. Struct.Mol. Biol. 20 (3), 290–299. 10.1038/nsmb.2474 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chong S., Vickaryous N., Ashe A., Zamudio N., Youngson N., Hemley S., et al. (2007). Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat. Genet. 39 (5), 614–622. 10.1038/ng2031 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Czerwińska P., Mazurek S., Wiznerowicz M. (2017). The complexity of TRIM28 contribution to cancer. J. Biomed. Sci. 24 (1), 63. 10.1186/s12929-017-0374-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dalgaard K., Landgraf K., Heyne S., Lempradl A., Longinotto J., Gossens K., et al. (2016). Trim28 haploinsufficiency triggers Bi-stable epigenetic obesity. Cell 164 (3), 353–364. 10.1016/j.cell.2015.12.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Daxinger L., Whitelaw E. (2010). Transgenerational epigenetic inheritance: more questions than answers. Genome Res. 20 (12), 1623–1628. 10.1101/gr.106138.110 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Daxinger L., Oey H., Apedaile A., Sutton J., Ashe A., Whitelaw E. (2012). A forward genetic screen identifies eukaryotic translation initiation factor 3, subunit H (eIF3h), as an enhancer of variegation in the mouse. G3 (Bethesda, Md.) 2 (11), 1393–1396. 10.1534/g3.112.004036 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Daxinger L., Harten S. K. S. K., Oey H., Epp T., Isbel L., Huang E., et al. (2013). An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse. Genome Biol. 14 (9), R96. 10.1186/gb-2013-14-9-r96 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. de Angelis M. H., Flaswinkel H., Fuchs H., Rathkolb B., Soewarto D., Marschall S., et al. (2000). Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat. Genet. 25 (4), 444–447. 10.1038/78146 [DOI] [PubMed] [Google Scholar]
  23. Deichmann U. (2016). Epigenetics: the origins and evolution of a fashionable topic. Dev. Biol. 416 (1), 249–254. 10.1016/j.ydbio.2016.06.005 [DOI] [PubMed] [Google Scholar]
  24. Deichmann U. (2020). The social construction of the social epigenome and the larger biological context. Epigenetics and Chromatin 13 (1), 37. 10.1186/s13072-020-00360-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Desai V. P., Chouaref J., Wu H., Pastor W. A., Kan R. L., Oey H. M., et al. (2021). The role of MORC3 in silencing transposable elements in mouse embryonic stem cells. Epigenetics and Chromatin 14 (1), 49. 10.1186/s13072-021-00420-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Douse C. H., Tchasovnikarova I. A., Timms R. T., Protasio A. V., Seczynska M., Prigozhin D. M., et al. (2020). TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Nat. Commun. 11 (1), 4940. 10.1038/s41467-020-18761-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Duhl D. M. J., Vrieling H., Miller K. A., Wolff G. L., Barsh G. S. (1994). Neomorphic agouti mutations in obese yellow mice. Nat. Genet. 8 (1), 59–65. 10.1038/ng0994-59 [DOI] [PubMed] [Google Scholar]
  28. Elmer J. L., Hay A. D., Kessler N. J., Bertozzi T. M., Ainscough E. A. C., Ferguson-Smith A. C. (2021). Genomic properties of variably methylated retrotransposons in mouse. Mob. DNA 12 (1), 6. 10.1186/s13100-021-00235-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Felsenfeld G. (2014). A brief history of epigenetics. Cold Spring Harb. Perspect. Biol. 6 (1), a018200. 10.1101/cshperspect.a018200 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ferry L., Fournier A., Tsusaka T., Adelmant G., Shimazu T., Matano S., et al. (2017). Methylation of DNA ligase 1 by G9a/GLP recruits UHRF1 to replicating DNA and regulates DNA methylation. Mol. Cell 67 (4), 550–565.e5. 10.1016/j.molcel.2017.07.012 [DOI] [PubMed] [Google Scholar]
  31. Gapp K., Jawaid A., Sarkies P., Bohacek J., Pelczar P., Prados J., et al. (2014). Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17 (5), 667–669. 10.1038/nn.3695 [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Garrick D., Sutherland H., Robertson G., Whitelaw E. (1996). Variegated expression of a globin transgene correlates with chromatin accessibility but not methylation status. Nucleic Acids Res. 24 (24), 4902–4909. 10.1093/nar/24.24.4902 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Gilbert N., Marenduzzo D. (2025). Topological epigenetics: the biophysics of DNA supercoiling and its relation to transcription and genome instability. Curr. Opin. Cell Biol. 92, 102448. 10.1016/j.ceb.2024.102448 [DOI] [PubMed] [Google Scholar]
  34. Goodwin L. R., Picketts D. J. (2018). The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. Mol. Cell. Neurosci. 87, 55–64. 10.1016/j.mcn.2017.10.008 [DOI] [PubMed] [Google Scholar]
  35. Goto N., Suke K., Yonezawa N., Nishihara H., Handa T., Sato Y., et al. (2024). ISWI chromatin remodeling complexes recruit NSD2 and H3K36me2 in pericentromeric heterochromatin. J. Cell Biol. 223 (8), e202310084. 10.1083/jcb.202310084 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Greally J. M. (2018). A user’s guide to the ambiguous word “epigenetics.”. Nat. Rev. Mol. Cell Biol. 19 (4), 207–208. 10.1038/nrm.2017.135 [DOI] [PubMed] [Google Scholar]
  37. Groh S., Milton A. V., Marinelli L. K., Sickinger C. V., Russo A., Bollig H., et al. (2021). Morc3 silences endogenous retroviruses by enabling Daxx-mediated histone H3.3 incorporation. Nat. Commun. 12 (1), 5996. 10.1038/s41467-021-26288-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Gunasekara C. J., Maduranga U., Zhang T., Wells J. N., Baker M. S., Laritsky E., et al. (2025). Mouse metastable epialleles are extremely rare. Nucleic Acids Res. 53 (14), gkaf624. 10.1093/nar/gkaf624 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Gurzau A. D., Blewitt M. E., Czabotar P. E., Murphy J. M., Birkinshaw R. W. (2020). Relating SMCHD1 structure to its function in epigenetic silencing. Biochem. Soc. Trans. 48 (4), 1751–1763. 10.1042/BST20200242 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Hao F., Zhang Y., Hou J., Zhao B. (2025). Chromatin remodeling and cancer: the critical influence of the SWI/SNF complex. Epigenetics and Chromatin 18 (1), 22. 10.1186/s13072-025-00590-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Harten S. K., Bruxner T. J., Bharti V., Blewitt M., Nguyen T.-M.-T., Whitelaw E., et al. (2014). The first mouse mutants of D14Abb1e (Fam208a) show that it is critical for early development. Mamm. Genome 25 (7–8), 293–303. 10.1007/s00335-014-9516-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Harten S. K., Oey H., Bourke L. M., Bharti V., Isbel L., Daxinger L., et al. (2015). The recently identified modifier of murine metastable epialleles, rearranged L-Myc fusion, is involved in maintaining epigenetic marks at CpG island shores and enhancers. BMC Biol. 13 (1), 21. 10.1186/s12915-015-0128-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. He W., Dorn D. C., Erdjument-Bromage H., Tempst P., Moore M. A. S., Massagué J. (2006). Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell 125 (5), 929–941. 10.1016/j.cell.2006.03.045 [DOI] [PubMed] [Google Scholar]
  44. Heard E., Martienssen R. A. (2014). Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157 (1), 95–109. 10.1016/j.cell.2014.02.045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Henikoff S. (2023). The epigenetic landscape: an evolving concept. Front. Epigenetics Epigenomics 1, 1176449. 10.3389/freae.2023.1176449 [DOI] [Google Scholar]
  46. Herquel B., Ouararhni K., Khetchoumian K., Ignat M., Teletin M., Mark M., et al. (2011). Transcription cofactors TRIM24, TRIM28, and TRIM33 associate to form regulatory complexes that suppress murine hepatocellular carcinoma. Proc. Natl. Acad. Sci. 108 (20), 8212–8217. 10.1073/pnas.1101544108 [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Herridge R. P., Dolata J., Migliori V., de Santis Alves C., Borges F., Schorn A. J., et al. (2025). Pseudouridine guides germline small RNA transport and epigenetic inheritance. Nat. Struct. Mol. Biol. 32 (2), 277–286. 10.1038/s41594-024-01392-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Hollick J. B., Chandler V. L. (2001). Genetic factors required to maintain repression of a paramutagenic maize pl1 allele. Genetics 157 (1), 369–378. 10.1093/genetics/157.1.369 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Horsthemke B. (2018). A critical view on transgenerational epigenetic inheritance in humans. Nat. Commun. 9 (1), 2973. 10.1038/s41467-018-05445-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Huang Z., Cui W., Ratnayake I., Gallik K. L., Cohen L., Tawil R., et al. (2025). SMCHD1 maintains heterochromatin, genome compartments and epigenome landscape in human myoblasts. Nat. Commun. 16 (1), 6900. 10.1038/s41467-025-62211-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Isbel L., Srivastava R., Oey H., Spurling A., Daxinger L., Puthalakath H., et al. (2015). Trim33 binds and silences a class of young endogenous retroviruses in the mouse testis; a novel component of the arms race between retrotransposons and the host genome. PLOS Genet. 11 (12), e1005693. 10.1371/journal.pgen.1005693 [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Isbel L., Prokopuk L., Wu H., Daxinger L., Oey H., Spurling A., et al. (2016). Wiz binds active promoters and CTCF-binding sites and is required for normal behaviour in the mouse. ELife 5, e15082. 10.7554/eLife.15082 [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Jablonka E. (2013). Epigenetic inheritance and plasticity: the responsive germline. Prog. Biophysics Mol. Biol. 111 (2–3), 99–107. 10.1016/j.pbiomolbio.2012.08.014 [DOI] [PubMed] [Google Scholar]
  54. Jablonka E. (2017). The evolutionary implications of epigenetic inheritance. Interface Focus 7 (5), 20160135. 10.1098/rsfs.2016.0135 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Justice M., Carico Z. M., Stefan H. C., Dowen J. M. (2020). A WIZ/Cohesin/CTCF complex anchors DNA loops to define gene expression and cell identity. Cell Rep. 31 (2), 107503. 10.1016/j.celrep.2020.03.067 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Kaati G., Bygren L. O., Pembrey M., Sjöström M. (2007). Transgenerational response to nutrition, early life circumstances and longevity. Eur. J. Hum. Genet. 15 (7), 784–790. 10.1038/sj.ejhg.5201832 [DOI] [PubMed] [Google Scholar]
  57. Kazachenka A., Bertozzi T. M., Sjoberg-Herrera M. K., Walker N., Gardner J., Gunning R., et al. (2018). Identification, characterization, and heritability of murine metastable epialleles: implications for non-genetic inheritance. Cell 175 (5), 1259–1271.e13. 10.1016/J.CELL.2018.09.043 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Kim Y., Ha N. Y., Kang M.-S., Ryu E., Yi G., Yoo J., et al. (2024). ATAD5-BAZ1B interaction modulates PCNA ubiquitination during DNA repair. Nat. Commun. 15 (1), 10496. 10.1038/s41467-024-55005-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Kumar R., Cheok C. F. (2014). RIF1: a novel regulatory factor for DNA replication and DNA damage response signaling. DNA Repair 15, 54–59. 10.1016/j.dnarep.2013.12.004 [DOI] [PubMed] [Google Scholar]
  60. Mangiavacchi A., Morelli G., Orlando V. (2023). Behind the scenes: how RNA orchestrates the epigenetic regulation of gene expression. Front. Cell Dev. Biol. 11, 1123975. 10.3389/fcell.2023.1123975 [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Masutani M., Sonenberg N., Yokoyama S., Imataka H. (2007). Reconstitution reveals the functional core of mammalian eIF3. EMBO J. 26 (14), 3373–3383. 10.1038/sj.emboj.7601765 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Mishima Y., Miyagi S., Saraya A., Negishi M., Endoh M., Endo T. A., et al. (2011). The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis. Blood 118 (9), 2443–2453. 10.1182/blood-2011-01-331892 [DOI] [PubMed] [Google Scholar]
  63. Miska E. A., Ferguson-Smith A. C. (2016). Transgenerational inheritance: models and mechanisms of non–DNA sequence–based inheritance. Science 354 (6308), 59–63. 10.1126/science.aaf4945 [DOI] [PubMed] [Google Scholar]
  64. Morgan H. D., Sutherland H. G. E., Martin D. I. K., Whitelaw E. (1999). Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23 (3), 314–318. 10.1038/15490 [DOI] [PubMed] [Google Scholar]
  65. Murray K. O., Clanton T. L., Horowitz M. (2022). Epigenetic responses to heat: from adaptation to maladaptation. Exp. Physiol. 107 (10), 1144–1158. 10.1113/EP090143 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Nolan P. M., Peters J., Strivens M., Rogers D., Hagan J., Spurr N., et al. (2000). A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat. Genet. 25 (4), 440–443. 10.1038/78140 [DOI] [PubMed] [Google Scholar]
  67. Oppikofer M., Bai T., Gan Y., Haley B., Liu P., Sandoval W., et al. (2017). Expansion of the ISWI chromatin remodeler family with new active complexes. EMBO Rep. 18 (10), 1697–1706. 10.15252/embr.201744011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Padeken J., Methot S. P., Gasser S. M. (2022). Establishment of H3K9-methylated heterochromatin and its functions in tissue differentiation and maintenance. Nat. Rev. Mol. Cell Biol. 2022, 1–18. 10.1038/s41580-022-00483-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Pembrey M. E., Bygren L. O., Kaati G., Edvinsson S., Northstone K., Sjöström M., et al. (2006). Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14 (2), 159–166. 10.1038/sj.ejhg.5201538 [DOI] [PubMed] [Google Scholar]
  70. Perez M. F., Lehner B. (2019). Intergenerational and transgenerational epigenetic inheritance in animals. Nat. Cell Biol. 21, 143–151. 10.1038/s41556-018-0242-9 [DOI] [PubMed] [Google Scholar]
  71. Poleshko A., Kossenkov A. V., Shalginskikh N., Pecherskaya A., Pecherskaya A., Einarson M. B., et al. (2014). Human factors and pathways essential for mediating epigenetic gene silencing. Epigenetics 9 (9), 1280–1289. 10.4161/epi.32088 [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Preis J. I., Downes M., Oates N. A., Rasko J. E. J., Whitelaw E. (2003). Sensitive flow cytometric analysis reveals a novel type of parent-of-origin effect in the mouse genome. Curr. Biol. 13 (11), 955–959. 10.1016/S0960-9822(03)00335-X [DOI] [PubMed] [Google Scholar]
  73. Rakyan V. K., Blewitt M. E., Druker R., Preis J. I., Whitelaw E. (2002). Metastable epialleles in mammals. Trends Genet. 18 (7), 348–351. 10.1016/S0168-9525(02)02709-9 [DOI] [PubMed] [Google Scholar]
  74. Rakyan V. K., Chong S., Champ M. E., Cuthbert P. C., Morgan H. D., Luu K. V. K., et al. (2003). Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc. Natl. Acad. Sci. U. S. A. 100 (5), 2538–2543. 10.1073/pnas.0436776100 [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Rastan S., Robertson E. (2001). Rosa Beddington (1956–2001). Nature 412 (6843), 138. 10.1038/35084325 [DOI] [PubMed] [Google Scholar]
  76. Reuter G., Spierer P. (1992). Position effect variegation and chromatin proteins. BioEssays 14 (9), 605–612. 10.1002/bies.950140907 [DOI] [PubMed] [Google Scholar]
  77. Robertson G., Garrick D., Wu W., Kearns M., Martin D., Whitelaw E. (1995). Position-dependent variegation of globin transgene expression in mice. Proc. Natl. Acad. Sci. 92 (12), 5371–5375. 10.1073/pnas.92.12.5371 [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Roth G. V., Gengaro I. R., Qi L. S. (2024). Precision epigenetic editing: technological advances, enduring challenges, and therapeutic applications. Cell Chem. Biol. 31 (8), 1422–1446. 10.1016/j.chembiol.2024.07.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Santilli F., Boskovic A. (2023). Mechanisms of transgenerational epigenetic inheritance: lessons from animal model organisms. Curr. Opin. Genet. Dev. 79, 102024. 10.1016/j.gde.2023.102024 [DOI] [PubMed] [Google Scholar]
  80. Sapozhnikov D. M., Szyf M. (2024). Genetic confounds of transgenerational epigenetic inheritance in mice. Epigenetics 19 (1), 2318519. 10.1080/15592294.2024.2318519 [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Schall P. Z., Ruebel M. L., Latham K. E. (2019). A new role for SMCHD1 in life’s master switch and beyond. Trends Genet. 35 (12), 948–955. 10.1016/j.tig.2019.10.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Schotta G., Ebert A., Dorn R., Reuter G. (2003). Position-effect variegation and the genetic dissection of chromatin regulation in drosophila. Seminars Cell and Dev. Biol. 14 (1), 67–75. 10.1016/S1084-9521(02)00138-6 [DOI] [PubMed] [Google Scholar]
  83. Soewarto D., Fella C., Teubner A., Rathkolb B., Pargent W., Heffner S., et al. (2000). The large-scale munich ENU-mouse-mutagenesis screen. Mamm. Genome 11 (7), 507–510. 10.1007/s003350010097 [DOI] [PubMed] [Google Scholar]
  84. Sorolla A., Tallack M. R., Oey H., Harten S. K., Daxinger L. C., Magor G. W., et al. (2015). Identification of novel hypomorphic and null mutations in Klf1 derived from a genetic screen for modifiers of α-globin transgene variegation. Genomics 105 (2), 116–122. 10.1016/j.ygeno.2014.09.013 [DOI] [PubMed] [Google Scholar]
  85. Sorolla M. A., Marqués M., Parisi E., Sorolla A. (2021). An N-ethyl-N-Nitrosourea mutagenesis screen in mice reveals a mutation in nuclear respiratory factor 1 (Nrf1) altering the DNA methylation state and correct embryonic development. Animals 11 (7), 2103. 10.3390/ani11072103 [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Strahl B. D., Allis C. D. (2000). The language of covalent histone modifications. Nature 403 (6765), 41–45. 10.1038/47412 [DOI] [PubMed] [Google Scholar]
  87. Szklarczyk D., Kirsch R., Koutrouli M., Nastou K., Mehryary F., Hachilif R., et al. (2023). The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51 (D1), D638–D646. 10.1093/nar/gkac1000 [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Takahashi Y., Valencia M. M., Yu Y., Ouchi Y., Takahashi K., Shokhirev M. N., et al. (2023). Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice. Cell 0 (0). 10.1016/J.CELL.2022.12.047 [DOI] [PubMed] [Google Scholar]
  89. Tapia del Fierro A., den Hamer B., Benetti N., Jansz N., Chen K., Beck T., et al. (2023). SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease. Nat. Commun. 14 (1), 5466. 10.1038/s41467-023-40992-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Tatarakis A., Saini H., Yu J., Feng W., Pinzon-Arteaga C. A., Moazed D. (2025). Requirements for establishment and epigenetic stability of mammalian heterochromatin. Mol. Cell 85 (18), 3388–3406.e12. 10.1016/j.molcel.2025.08.025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Torres-Padilla M. E., Zernicka-Goetz M. (2006). Role of TIF1α as a modulator of embryonic transcription in the mouse zygote. J. Cell Biol. 174 (3), 329–338. 10.1083/jcb.200603146 [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Waddington C. H. (1942). The epigenotype. Endeavour 41, 18–20. 10.1093/ije/dyr184 [DOI] [PubMed] [Google Scholar]
  93. Weaver I. C. G., Cervoni N., Champagne F., D’Alessio A. C., Sharma S., Seckl J. R., et al. (2004). Epigenetic programming by maternal behavior. Nat. Neurosci. 7 (8), 847–854. 10.1038/nn1276 [DOI] [PubMed] [Google Scholar]
  94. Wei K., Li R., Zhao X., Xie B., Xie T., Sun Q., et al. (2025). TRIM28 is an essential regulator of three-dimensional chromatin state underpinning CD8+ T cell activation. Nat. Commun. 16 (1), 750. 10.1038/s41467-025-56029-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Weismann A. (1893). The germ-plasm: a theory of heredity. New york, NY: Scribner’s. Available online at: https://www.biodiversitylibrary.org/bibliography/11331 [Google Scholar]
  96. Whitelaw E. (2015). Disputing Lamarckian epigenetic inheritance in mammals. Genome Biol. 16 (1), 60. 10.1186/s13059-015-0626-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Whitelaw E., Lamb P., Hogben P., Proudfoot N. J. (1989). The globin switch at the level of mRNA in the developing mouse. Prog. Clin. Biol. Res. 316A, 323–333. [PubMed] [Google Scholar]
  98. Whitelaw N. C., Chong S., Morgan D. K., Nestor C., Bruxner T. J., Ashe A., et al. (2010). Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise. Genome Biol. 11 (11), R111. 10.1186/gb-2010-11-11-r111 [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Wolff G. L., Kodell R. L., Moore S. R., Cooney C. A. (1998). Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12 (11), 949–957. 10.1096/fasebj.12.11.949 [DOI] [PubMed] [Google Scholar]
  100. Youngson N. A., Vickaryous N., van der Horst A., Epp T., Harten S., Fleming J. S., et al. (2011). A missense mutation in the transcription factor Foxo3a causes teratomas and oocyte abnormalities in mice. Mamm. Genome 22 (3–4), 235–248. 10.1007/s00335-011-9317-7 [DOI] [PubMed] [Google Scholar]
  101. Youngson N. A., Epp T., Roberts A. R., Daxinger L., Ashe A., Huang E., et al. (2013). No evidence for cumulative effects in a Dnmt3b hypomorph across multiple generations. Mamm. Genome 24 (5–6), 206–217. 10.1007/s00335-013-9451-5 [DOI] [PubMed] [Google Scholar]
  102. Yu C., Ding Z., Liang H., Zhang B., Chen X. (2019). The roles of TIF1γ in cancer. Front. Oncol. 9, 979. 10.3389/fonc.2019.00979 [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Zhang Y., Bertulat B., Tencer A. H., Ren X., Wright G. M., Black J., et al. (2019). MORC3 forms nuclear condensates through phase separation. IScience 17, 182–189. 10.1016/j.isci.2019.06.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Zhang Q., Dang W., Wang M. C. (2025). Lysosomes signal through the epigenome to regulate longevity across generations. Science 389 (6767), 1353–1360. 10.1126/science.adn8754 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Articles from Frontiers in Epigenetics and Epigenomics are provided here courtesy of Frontiers Media SA

RESOURCES