The MORC family

Abstract

Microrchidia (MORC) is a highly conserved nuclear protein superfamily with widespread domain architectures that intimately link MORCs with signaling-dependent chromatin remodeling and epigenetic regulation. Accumulating structural and biochemical evidence has shed new light on the mechanistic action and emerging role of MORCs as epigenetic regulators in diverse nuclear processes. In this Point of View, we focus on discussing recent advances in our understanding of the unique domain architectures of MORC family of chromatin remodelers and their potential contribution to epigenetic control of DNA template-dependent processes such as transcription and DNA damage response. Given that the deregulation of MORCs has been linked with human cancer and other diseases, further efforts to uncover the structure and function of MORCs may ultimately lead to the development of new approaches to intersect with the functionality of MORC family of chromatin remodeling proteins to correct associated pathogenesis.

Introduction

Microrchidia (MORC) is a relatively uncharacterized, highly conserved nuclear protein family from prokaryotic to eukaryotic cells.^1,2 To date, there are five members of the MORC family in humans, namely, MORC1 (also called MORC, ZCW6 or CT33), MORC2 (ZCW3, ZCWCC1, KIAA0852 or AC004542.C22.1), MORC3 (ZCW5, ZCWCC3, NXP2 or KIAA0136), MORC4 (ZCW4, ZCWCC2, FLJ11565 or dJ75H8.2) and the divergent SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) (KIAA0650) with chromosome condensation protein SMC-type hinge domains in addition to the MORC module (www.genecards.org).^1,3-5

Emerging evidence shows that members of the MORC protein superfamily exert tissue-specific expression patterns with a wide range of biological functions (Table 1). In this context, it was initially thought that MORC1 is primarily expressed in male germ cells and regulates mammalian germ cell development and meiosis.^3,6 However, recent studies provided the evidence that MORC1 is frequently expressed in multiple myeloma cells⁷ and is frequently mutated in primary and metastatic estrogen receptor-positive lobular breast cancers.⁸ In contrast, MORC2 is ubiquitously expressed in human cells and tissues.^4,16,17 Gene expression profiling studies revealed that the levels of MORC2 expression are upregulated in breast cancer tissues and in situ carcinomas, as compared with adjacent normal breast tissues,⁹ and associated with the recurrence of triple-negative breast cancer.¹⁰

Table 1. Expression patterns of MORCs.

	Expression patterns	Functions	References
MORC1	Specific expression in male germ cells	Spermatogenesis	3 , 6
	Frequent expression in multiple myeloma cells	Unknown	7
	Mutation in lobular breast tumors	Unknown	8
MORC2	Upregulation in breast cancer tissues and in situ carcinomas	Association with the recurrence of triple-negative breast cancers	9 , 10
MORC3	Co-localization with PML-NBs	Regulation of p53 activity and induction of cellular senescence	11 , 12
	Altered expression following chemotherapy agent treatment	Unknown	13
MORC4	High expression in diffuse large B-cell lymphomas patients and in multiple B-cell lymphoma-derived cell lines	Unknown	14
SMCHD1	Ubiquitous expression in mammalian cells	A causal genetic determinant of FSHD2	15
		Tumor suppressor	24

PML-NBs, promyelocytic leukemia-nuclear bodies; FSHD2, facioscapulohumeral muscular dystrophy type 2.

Promyelocytic leukemia-nuclear body (PML-NB) is a dynamic subnuclear macromolecular structure formed by PML and Sp100 proteins and has been implicated in the regulation of diverse cellular functions, including transcription, DNA repair and tumor suppression.^18-20 Interestingly, MORC3 has been shown to localize on PML-NBs and to induce p53-dependent premature senescence through regulating p53 activation and localization into PML-NBs.¹¹ More recent studies demonstrated a two-step mechanism involved in the co-localization of MORC3 with PML-NBs.¹² In this context, MORC3 functions as a “molecular clamp” through the ATPase cycle to form MORC3 nuclear domains in a PML-independent manner. MORC3 also associates with PML via its sumoylation modification.¹² Given that many of the proteins that accumulate in PML-NBs are putative epigenetic factors such as histone methyltransferases, histone deacetylases or DNA methyltransferases,²¹ it is conceivable that MORC3 is likely to be an epigenetic regulator in diverse biological processes. In addition, it is interesting to note that the expression of MORC3 is significantly altered in normal peripheral blood leukocytes following treatment with chemotherapy agents, but its suspected role in chemotherapy response remains to be determined.¹³ In contrast, MORC4 mRNA is widely expressed at low levels in normal tissues, with highest expression levels in placenta and testis.¹⁴ Recently, MORC4 has been identified as a potential lymphoma biomarker, as it is highly expressed in about 66% diffuse large B-cell lymphomas patients and in multiple B-cell lymphoma-derived cell lines.¹⁴ However, the functional role and the underlying mechanism of MORC4 in the development and progression of lymphoma remain unexplored.

SMCHD1 belongs to the structural maintenance of chromosome (SMC) gene superfamily that plays fundamental roles in higher-order chromosome organization and dynamics.^22,23 Protein sequence analysis revealed that mouse Smchd1 shares 86% sequence identity with its human homolog.²⁴ SMCHD1 has been recently identified as a causal genetic determinant of facioscapulohumeral dystrophy type 2¹⁵ as well as a potential tumor suppressor in human cancers.²⁴ It is noteworthy to mention that SMCHD1, like MORC3,¹² is a potential substrate of sumoylation,²⁵ but whether and how the sumoylation modification plays a role in the regulation of SMCHD1 function under physiological and pathophysiological conditions remains to be tested.

The accumulating structural and biochemical evidence has provided new perspective about the mechanism of action and functions of MORCs. In particular, MORCs are becoming increasingly recognized as new epigenetic regulators of fundamental biological processes.^4,26 In the following sections, we discuss recent advances in our understanding of the domain architectures of MORCs, the intriguing roles of MORCs in epigenetic regulation of transcription and DNA damage response, and the potential connection between these two processes.

Domain Architectures of MORCs

GHKL-type ATPase domain

One characteristic of the MORC protein family is the presence at the N-terminus of a highly conserved GHKL (DNA gyrase, hsp90, histidine kinase and DNA mismatch repair enzyme MutL) domain combined to a carboxyl-terminal S5 domain^1-3,27 (Fig. 1A). The GHKL domain contains conserved ATP binding motifs, and the S5 domain usually provides a conserved basic residue that functions similarly to the arginine or lysine finger observed in various phosphorylation reaction.¹ Thus, the GHKL+ S5 domain constitutes an active GHKL-type ATPase module that is involved in ATP binding and hydrolysis and plays crucial roles in DNA metabolism and signaling transduction.^1,2,28 In contrast, the ATPase subunits of the well-characterized, four classes of chromatin remodeling complexes including SWI/SNF (SWItch/sucrose nonfermentable), ISWI (imitation switch), CHD (chromodomain, helicase, DNA binding) and INO80 (inositol requiring 80) contain a common Snf2-like ATPase domain^29,30 (Fig. 1B). Interestingly, the GHKL-type ATPase is also found in other prokaryotic and eukaryotic chromatin-related proteins, such as heat shock protein 90,³¹ DNA repair proteins of the MutL family,^1,32,33 the ATPase subunits of the topoisomerases,³⁴ SMCHD family member GMI1 (gamma-irradiation and mitomycin C induced 1) in Arabidopsis thaliana³⁵ and defective in meristem silencing 11 (DMS11) in Arabidopsis thaliana.³⁶ It has been shown that the MORC ATPase is involved in gene silencing in Arabidopsis thaliana^26,36 and in the regulation of chromatin architecture in response to DNA damage signals in human cells⁴ (Table 2). Thus, the GHKL-type ATPase module is becoming a new player in epigenetic regulation of transcription and DNA damage response in plants and mammals.

Figure 1. Comparison of the domain architecture between the MORC family (A) and the well-characterized four classes of chromatin remodeling complexes (B). (A) Members of the MORC family contain a conserved GHKL-type ATPase domain at their N-terminus, a PHD-X/ZF-CW domain in their midst and varied coiled-coil domains. In addition, MORC2 protein contains a chromo-like domain at its carboxy-terminus. (B) The ATPase subunits of the four classes of chromatin remodeling complexes including SWI/SNF (SWItch/sucrose non-fermentable), ISWI (imitation switch), CHD (chromodomain, helicase, DNA binding) and INO80 (inositol requiring 80) contain a common Snf2-like ATPase domain and other functional domains as indicated.^29,30

Table 2. Domain architectures of MORCs.

Domain architectures	Functions	References
GHKL-type ATPase domain	Gene silencing in Arabidopsis thaliana	26 , 36
	DNA damage response	4
PHD-X/ZF-CW domain	Histone recognition module for methylated histone H3 lysine 4	37 - 39
Chomo-like domain	Unknown	-
Coiled-coil domain	Unknown	-

PHD-X/ZF-CW domain

In addition to the GHKL-ATPase domain, different members of the MORC family show fusions to other domains that play a critical role in recognizing different epigenetic marks on DNA.^4,40 In this context, another widespread domain of the MORC proteins is a carboxyl-terminal PHD-X/ZF-CW domain⁴⁰ (Fig. 1A). The ZF-CW domain is a motif of about 60 amino acids comprising at least four cysteine (C) and two tryptophan (W) residues that is frequently found in proteins involved in epigenetic regulation.^37,38,40 This domain is an N-terminally truncated version of the zinc-binding PHD (plant homeodomain) finger domain that lacks the first and third metal-chelating dyads of the binuclear treble clef fold.^37,41 Despite this structural modification, it retains the histone H3 binding interface and predominantly functions as a methylated H3K4 binding domain, similar to the conventional PHD domain^2,37-39,41 (Table 2).

In addition to MORCs, the ZF-CW domain is also present in other chromatin-related factors (www.uniprot.org/uniprot), such as Arabidopsis thaliana histone-lysine N-methyltransferase ASHH2,⁴² HSI2 (high-level expression of sugar-inducible gene 2), HSL1 (HSI2-like 1),^43,44 methyl-CpG-binding domain-containing protein 1 (AtMBD1), AtMBD2, AtMBD3, AtMBD4, AtMBD12,^45,46 human lysine-specific histone demethylase 1B (KDM1B) (also known as LSD2 or AOF1),^47,48 zinc finger CW-type PWWP domain protein 1 protein 1 (ZCWPW1)³⁷ and ZCWPW2. Recent studies have shown that HSL1 interacts with histone deacetylase 19 (HDA19) through its ZF-CW domain and recruits HDA19 to repress the expression of seed maturation genes in seedlings.⁴³ In addition, KDM1B contains a unique N-terminal ZF-CW domain that is not present in KDM1A (also known as LSD1 or AOF2)^47,49 and is required for its demethylase activity and transcriptional repression activity.^49,50 Furthermore, structural and biochemical evidence has shown that the ZF-CW domains of ASHH2, ZCWPW1, MORC3, MORC4 and HSI2 proteins are novel histone recognition modules with specifically for methylated histone H3 lysine 4,^37-39 but their binding preference for the histone H3 methylation status may vary in different proteins.³⁸ These observations suggest that the ZF-CW domain is involved in chromatin regulation through the recognition of epigenetic signals.³⁷

Chomo-like domain

The chromo-like domain is a widely distributed sequence motif comprising about 40–50 amino acids and is involved in the epigenetic regulation of heterochromatin function and euchromatic gene expression.^51-53 Computational analysis of MORC2 sequence, through a hidden Markov model search using the JACKHMMER program (hmmer.janelia.org) for further conserved domains that might have previously eluded detection, recognized a novel chromo-like domain that recovers the first chromo-like domain of histone methylase SETDB1⁵⁴ (Fig. 1A). All elements comprising the core SH3-like fold of the chromo-like domains are conserved in the version of the domain found in MORC2,⁴¹ suggesting that it is likely to bind to lysines in histones. Chromo-like domain is widely present in various chromatin-associated proteins in humans (www.uniprot.org/uniprot), such as the chromodomain-helicase-DNA-binding (CHD) protein family members (CHD1–9), chromobox protein homolog (CBX) family members (CBX1–8), histone acetyltransferases KAT5 and KAT8, histone methyltransferases SUV39H1 and SUV39H2, SWI/SNF complex subunits SMARCC1 and SMARCC2, AT-rich interactive domain-containing protein 4A (ARID4A), ARID4B, chromodomain Y-like protein 2 (CDYL2), testis-specific chromodomain protein Y 1 (CDY1), CDY2, M-phase phosphoprotein 8 (MPHOSPH8), male-specific lethal 3 homolog (MSL3) and mortality factor 4 like 1(MORF4L1).^51-53 These proteins have been widely documented with respect to dominant functions in chromatin remodeling and the regulation of gene expression in health and disease.^51-53 However, the function and mechanism of action of the chromo-like domain in MORC2 protein have not yet been elucidated.

Coiled-coil domain

The coiled-coil domain typically consists of two to five α-helices wrapped around each other into super-helical structures and is found in about 10% of all protein sequences.^55-57 Accumulating evidence has suggested that the coiled-coil domain is an important structural determinant for the regulation of protein-protein and protein-DNA interaction,^57-66 protein stability,^67,68 protein functional activation,^65,69 subcellular localization,^65,70-72 gene transcription,^73,74 DNA damage response^75-78 and signaling transduction.^66,79-83 Interestingly, MORC1 and MORC2 contain the predicted three-stranded coiled-coil domain that is absent in both MORC3 and MORC4 proteins.⁴⁰ Instead, MORC3 and MORC4 have an additional two-stranded coiled-coil motif near their carboxyl-terminus⁴⁰(Fig. 1A). However, the implication of these conserved coiled-coil domains in emerging MORC functions remains to be investigated.

Collectively, recent structural and biochemical studies have defined MORCs as potential epigenetic regulators of many basic biological processes. It is becoming increasingly clear that crosstalk between different structural domains plays an important role in the regulation of protein functions. One case in point is the human chromatin remodeler CHD4, whose PHD and chromo domains associate with its ATPase motif and regulate its ATPase activity.⁸⁴ However, it remains unclear whether and how these structural domains of MORCs act in concert to govern their biological functions in response to extracellular and intracellular stimuli. Interestingly, our recent study revealed that signaling-dependent phosphorylation of MORC2 at lysine 739 that localizes between the PHD-X/ZF-CW domain and the chromo-like domain controls its ATPase activity responsible for chromatin remodeling in response to DNA damage signals, but he mechanastic detail remains elusive.⁴

Functions of MORCs

MORCs and transcription

Accumulating evidence suggests that MORCs play a conserved role in transcription (Table 3). In this context, two Arabidopsis genes, AtMORC1 (also known as CRT1) and AtMORC6 (also known as DMS11) are involved in heterochromatin condensation and gene silencing in Arabidopsis thaliana.²⁶ Arabidopsis thaliana CRT1 (compromised for recognition of Turnip Crinkle virus) is a prototypic eukaryotic member of the MORC superfamily with a conserved GHKL-ATPase motif.^27,89 It has been recently shown that CRT1 binds DNA, exhibits endonuclease activity, and has important nuclear functions during immune response.⁸⁸ In contrast, DMS11 is a GHKL-type ATPase that is also involved in RNA-directed DNA methylation in Arabidopsis thaliana.³⁶ In this context, DMS11 interacts with DMS3, which lacks ATPase motif, and provides the missing ATPase function for DMS3, and consequently, cooperate in the RNA-directed DNA methylation pathway to promote transcriptional repression.³⁶

Table 3. Functions of MORCs in transcription and DNA damage response.

	MORCs	Functions	References
Transcription	MORC2	Transcription repression of CAIX gene	16
	MORC3	SUMO-mediated transcriptional repression	85
	SMCHD1	X inactivation and CpG island hypermethylation	22 , 86
	DMS3 (Arabidopsis)	RNA-mediated DNA methylation	36 , 87
	AtMORC1 (CRT1)	Heterochromatin condensation and gene silencing	26
	AtMORC6 (DMS11)	Heterochromatin condensation and gene silencing	26
		RNA-directed DNA methylation	36
DDR	MORC2	Chromatin remodeling and DNA repair	4
	AtMORC1 (CRT1)	Tolerance to DNA-damage agent mitomycin C	88
	GMI1 (Arabidopsis)	Repair of DNA double-strand breaks	35

CAIX, carbonic anhydrase IX; DMS, defective in meristem silencing; GMI1, gamma-irradiation and mitomycin C induced 1.

Similarly, MORC2 has been shown to repress carbonic anhydrase IX (CAIX) gene expression in gastric cancer cells through interacting with and recruiting histone deacetylase 4 (HDAC4) onto the CAIX promoter.¹⁶ In addition, MORC3 is a nuclear matrix-associated protein with RNA binding activity, raising the possibility that MORC3 might have a novel function in nuclear RNA metabolism.⁵ In support of this notion, MORC3 associates with SUMO-2 and is required for transcriptional repression.⁸⁵

Consistent with the above observations, SMCHD1 has a critical role in epigenetic gene silencing.²² In this context, SMCHD1 localizes to the inactive X chromosome and has a critical role in the maintenance of X inactivation and the hypermethylation of CpG islands (CGIs).²² A recent study further pointed out that inactive X chromosome CpG island methylation occurs via either Smchd1-dependent or independent pathway.⁸⁶ In this context, a subset of CGIs is methylated at a relatively fast rate following the onset of X inactivation that is independent of the chromosomal protein Smchd1 in many cases. In contrast, methylation of other CGIs proceeds relatively slowly and requires Smchd1.⁸⁶ Smchd1 has been recently identified as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of facioscapulohumeral dystrophy type 2.¹⁵ Interestingly, a recent study identified Smchd1 as a tumor suppressor in oncogene-driven models.²⁴ Lack of Smchd1 is not inherently oncogenic, but loss of Smchd1 accelerates Eμ-Myc-driven B-cell lymphomas by deregulating expression of a subset of Polycomb-repressive complex 2 and mixed lineage leukemia fusion protein target genes.²⁴ However, lack of Smchd1 does not affect overall telomere length in mice.⁹⁰ Interestingly, DMS3, a protein with homology to Smchd1 in Arabidopsis thaliana, has been shown to be required for RNA-mediated DNA methylation.⁸⁷ In support of this notion, the GHKL ATPase DMS11 physically interacts and cooperates with DMS3 in the RNA-mediated DNA methylation pathway to promote transcriptional repression.³⁶

MORC and DNA damage response (DDR)

Given their nuclear localization signals, MORCs have been predicted to be a component of the DNA damage response signaling network in addition to its role in transcription³ (Table 3). In support of this notion, CRT1 (AtMORC1) has been shown to enhance tolerance to DNA-damage agent mitomycin C, indicating that CRT1 is involved in DNA damage repair.⁸⁸ Our recent study discovered that MORC2 is activated via phosphorylation by extracellular DNA damage signals and facilitates an ATPase-dependent chromatin remodeling following DNA damage induction, thus promoting DNA double-strand break (DSB) repair and cell survival⁴ (Fig. 2).

Figure 2. Proposed model for the physiologic role of MORCs. MORCs control a variety of cellular and physiological functions in response to growth factor signaling, extracellular microenvironment, and genotoxic stress. Posttranslational modification of MORCs by upstream kinases might modulate their cellular functions. PAK1 phosphorylates MORC2 at serine 739 in response to both genotoxic stress and growth factor signaling and directs an effective DDR by an ATP-dependent chromatin remodeling event. Domain architecture of MORCs will provide essential insights into their specific and non-redundant roles in epigenetic regulation via recognition of various posttranslational modifications of histones or functional interactions with histone modifying enzymes. MORCs are deregulated in a variety of cancers and possibly function as a critical balance for efficient crosstalk between growth factor signaling and DDR. Collectively, these will contribute to adaptive survival strategies and therapy resistance often observed in cancer. DDR, DNA damage response.

The histone variant H2AX is a key chromatin component in cellular responses to DSBs and, in particular, the phosphorylation of H2AX (termed γH2AX) by the phosphatidylinositol 3-kinase-related kinases (PIKKs) ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR) and DNA-dependent protein kinase (DNA-PK) is a specific and key coordinator of DDR signaling.^91-94 Our laboratory has recently demonstrated that MORC2 promotes the induction of γH2AX following DNA damage, but has no any effect on the expression and activation of the ATM, ATR, DNA-PK protein kinases.⁴ Similarly, the well-characterized SWI/SNF chromatin remodeling complex regulates DNA damage-induced γH2AX induction, but does not affect the expression of the above mentioned PIKK kinases, or their activation and/or recruitment to DSBs.⁹⁵ Thus, a functional crosstalk between the MORC2-containing complex and the SWI/SNF complex in recognition and signaling of DSBs in the context of chromatin remains to be investigated in the future.⁴ In addition, it has been well documented that the INO80 chromatin remodeling complex is recruited to DSB sites through its interaction with γH2AX.^96,97 Thus, it will be interesting to examine whether MORC2-containing chromatin remodeling complex is recruited to DNA damage sites and whether this recruitment depends on its interaction with γH2AX.

Another interesting finding is that MORC2 exerts a histone exchange activity that enables to replace the nucleosomal H2AZ-H2B dimer with the canonical H2A-H2B dimer in a phosphorylation- and ATPase-dependent manner.⁴ However, the functional implication of MORC2-mediated histone exchange in DSB repair or other basic biological processes remains largely unknown. Interestingly, a recent study revealed that the p400 remodeling ATPase utilizes its ATPase activity to exchange histone H2AZ onto nucleosomes at DSBs.⁹⁸ Moreover, the H2AZ exchange promotes specific patterns of histone modification and regulates the loading of the DSB repair complexes at DSBs, thus contributing to DSB repair.⁹⁸ Similarly, the INO80 chromatin remodeling complex also has a histone-exchange activity that exchanges nucleosomal H2AZ-H2B with free H2A-H2B dimers to promote genome stability.⁹⁹ In S. cerevisiae, the SWR1 chromatin remodeling complex catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ (S. cerevisiae Htz1) that is closely linked to the tight regulation of transcription and genetic stability.^100,101 Given these interestingly observations, it will be important to examine whether and how the MORCs and other chromatin remodeling complexes coordinately reorganize chromatin architecture in response to DNA damage and other stresses.

In addition, given that MORC3 localizes on PML-NBs,^11,12 which are intrinsic elements of the cellular response to DNA damage,^12,102 it would be exciting to examine whether MORC3 is implicated in DNA damage response in the future. In addition, GMI1, a GHKL-type ATPase domain containing protein in Arabidopsis and the homologs of mammalian SMCHD1, is induced by γ-irradiation in an ataxia telangiectasia mutated (ATM)-dependent manner and involved in the repair of DNA double-strand breaks, presumably, by homologous recombination.³⁵ However, it remains unknown whether the mammalian SMCHD1 plays a role in DNA repair in addition to its known function in X-inactivation.³⁵

MORCs: Moving Forward

The evolutionary contextual and gene neighborhood studies on prokaryotic MORCs and their eukaryotic relatives as well as recently emerging structural and biochemical evidence have defined MORCs as new players in epigenetic regulators of genome.^{1,2,4,26,37,38} Despite these great strides a detailed comprehensive analysis to delineate distinct non-redundant roles of these proteins in various cellular responses await functional and biochemical evaluation. To this end, a recent report by the authors has provided a first-of-its-kind, detailed biochemical analysis supporting the role and chromatin remodeling functions of MORC2 protein for optimal cellular response to genotoxic stress,⁴ and thereby established a functional link between this novel nucleosome-dependent ATPase and genome-surveillance mechanisms (Fig. 2). Intriguingly, MORC2’s ATPase-dependent chromatin remodeling function is dictated by upstream kinase dependent signaling in response to DNA-damage response and growth factor signaling.⁴ In light of our current knowledge, it is tempting to speculate that MORC2 may be a key epigenetic contributor in adaptive strategies employed by tumor cells for survival and therapy resistance. At the cellular level this can be achieved by efficiently integrating growth factor signaling with DNA repair processes. Mounting evidence suggests that MORCs play crucial roles in various cellular processes integral to maintain cellular homeostasis.

A closer analysis of MORC proteins and sequence comparison studies suggest the presence of conserved novel histone-recognition or sensing modules (Fig. 1). Chromatin remodelers like MORC2 function to alter nucleosomal structure of chromatin (Fig. 2). We predict that MORC proteins are likely to remodel nucleosomes with specific single or multivalent histone modifications utilizing unique histone-reading and -editing functions. We also suggest that MORCs may recognize similar or different single or combinatorial histone modifications and this, in turn, may impact the recognition patterns due to specific posttranslational modifications by upstream signaling events. Answers to these questions would fuel and shape future research to understand the physiological roles of these novel chromatin remodelers. Recent advancement in next-generation sequencing techniques like ChIP-Seq technology with robust supportive bioinformatics tools have provided novel insights to understand genome-wide recruitment patterns of various chromatin-interacting proteins at very high resolution. In this context, ChIP-Seq recruitment patterns of MORCs under defined experimental conditions combined with RNA sequencing of human cells with defined modulation of expression and functions of MORC2 have revealed a genome-wide footprint of MORC2 and its impact on gene expression and provided invaluable clues about “yet-to-be-discovered” targets and functions of MORC2 in eukaryotic cells (SSN, DQL and RK; unpublished data). Given that deregulation of MORCs has been linked with human cancers and other diseases,^{3,7,8,10,14,16,17,88} further studies may lead to better understanding of the components influenced by MORCs that could be targeted to reverse MORC-associated pathologic conditions. In closing, our understanding of the structural insights and physiological roles of eukaryotic MORCs and the contribution of the epigenome in the phenotypic outcome are likely to be merely the tip of the iceberg. Ongoing studies in our and other laboratories are addressing some of the emerging questions outlined here, with an aim to reveal molecular insights of the role of MORCs in transcription, chromatin looping, histone sensing and DNA repair.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.