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. Author manuscript; available in PMC: 2023 Sep 19.
Published in final edited form as: Nat Rev Cancer. 2021 May 17;21(7):413–430. doi: 10.1038/s41568-021-00357-x

Figure 2. Miswriting of chromatin modification promotes oncogenic development.

Figure 2.

a. Active enhancer is marked by H3K4me1 and H3K27ac, which are generated by mixed lineage leukemia 3 (MLL3) and MLL4, and histone acetyltransferases such as CREBBP and EP300. Enhancers are bound by transcription factors (TF), mediators and transcription coactivators such as BRD4, which activate RNA polymerase II (Pol II) for mediating productive transcription from promoters and generating enhancer RNA (eRNA) to facilitate gene activation. Enhancer-promoter looping underlies activation of gene transcription. Loss or inactivation mutation of CREBBP or EP300 and/or MLL3 or MLL4 is characteristic of cancers such as B-cell lymphoma, resulting in decreased H3K27ac and/or H3K4me1 at enhancers and reduced expression of genes related to tumor suppression, cell differentiation and/or antitumor immunity.

b. Wildtype MLL1 uses a N-terminal region for interacting with chromatin-binding cofactors, menin and PSIP1. MLL1 or its partial tandem duplication (PTD) results in elevated H3K4me3 at oncogenes such as HOX, promoting acute leukaemogenesis. MLL1 fusion oncoprotein gains a C-terminal segment from its fusion partner, such as AF9, ENL or AF4, which recruits DOT1L complex (DotCom) for catalyzing H3K79 methylation and/or the super elongation complex (SEC) for catalyzing serine 2 phosphorylation (Ser2ph) of the C-terminal domain (CTD) of RNA Polymerase II (Pol II). H3K79me and Pol-II CTD Ser2ph, possibly with other activators such as PAF1, promote expression of oncogenes such as those of the HOX family.

c. A collective action of wildtype EZH2 and its gain-of-function mutation, Y646X (X= F, C, H, S or N), causes abnormal elevation of H3K27me3 in lymphoma, leading to downregulation of transcripts related to cell cycle control and B cell differentiation.

d. Regulatory roles of H3K36me2/3 modifications at gene body, intergenic regions and CpG islands. First, intergenic H3K36me2, installed by NSD family proteins, and SETD2-mediated H3K36me3 at gene body both antagonizes H3K27me3. Meanwhile, H3K36me2/3 serves as a docking site of the DNMT3A/3B PWWP domain, resulting in co-localization of H3K36me2/3 with DNA 5mC at gene body and intergenic regions. Additionally, recognition of H3K36me3/2 by the Tudor domain of PHD finger protein 1 (PHF1) or PHF19 provides a possible mechanism for PRC2 complex to establish de novo H3K27me3. Deregulation of NSD family proteins, SETD2, PRC2, PHF1/19 and DNMT3A is frequent among various human tumors.

e. In breast cancer, overexpressed DOT1L interacts with MYC and EP300 to antagonize histone deacetylases (HDACs) and DNMT1, leading to the elevated H3K79me and H3Kac levels at epithelial-to-mesenchymal transition (EMT)-promoting oncogenes such as SNAIL and ZEB1.