Chromatin regulatory mechanisms and therapeutic opportunities in cancer

Abstract

Research over the past several decades has unmasked a major contribution of disrupted chromatin regulatory processes to human disease, particularly cancer. Advances in genome-wide technologies have highlighted frequent mutations in genes encoding chromatin-associated proteins, identified unexpected synthetic lethal opportunities and enabled increasingly comprehensive structural and functional dissection. Here, we review recent progress in our understanding of oncogenic mechanisms at each level of chromatin organization and regulation, and discuss new strategies towards therapeutic intervention.

Fig. 1 |. Chromatin regulatory processes in mammalian cells.

a, DNA is wrapped around a histone octamer containing two copies each of histones H2A, H2B, H3 and H4, forming the primary functional unit of chromatin: the nucleosome. Histone H1 binds to DNA at the entry and exit site of the nucleosome. b, DNA methylation is achieved by DNMTs, which are responsible for creating the 5mC mark, associated with transcriptional repression, and TET enzymes, which oxidize 5mC to create 5hmC, 5fC and 5caC. c, Histone modifications, such as acetylation (ac), methylation (me), ubiquitination (Ub) and phosphorylation (P), serve as instructive marks for both gene activation and gene repression. PRC2 and PRC1 deposit the H3K27me3 and H2AK119Ub marks, respectively, both of which correlate with transcriptional repression. d, Four families of ATP-dependent CRCs alter chromatin architecture by mobilizing, depositing or evicting nucleosomes. AURORA-B, Aurora kinase B; BRCA1, breast cancer type 1 susceptibility protein; CBP, CREB-binding protein; DUBs, deubiquitinating enzymes; GNAT, Gcn5-related N-acetyltransferases; HATs, histone acetyltransferases; ISWI, imitation SWI; KDMs, methyl demethylases; KMTs, methyl transferases; MSK1/2, mitogen- and stress-activated protein kinase 1/2; MST1, mammalian STE20-like protein kinase 1 (also known as STK4); PBRM1, protein polybromo-1; PRMTs, protein arginine N-methyltransferases; RSF1, remodelling and spacing factor 1; SIRT, sirtuin; TDG, thymine DNA glycosylase.

Fig. 2 |. DNMT and TET enzymes and related perturbations in AML.

a, Global hypomethylation and focal promoter/enhancer hypermethylation phenotypes are commonly detected in cancer. b, DNMT and TET enzymes are commonly mutated in adult AML and counteract one another via deposition or removal of the 5mC mark, respectively. DNMTs deposit a methyl group on to the carbon-5 position of cytosine using S-adenosyl-methionine (SAM) as a substrate, and TET enzymes rely on ɑ-ketoglutarate (ɑ-KG) and oxygen to oxidize 5mC and promote cytosine demethylation. c, IDH1/2 (encoding isocitrate dehydrogenase 1) mutations, which are common in AML, inhibit TET activity by converting the TET substrate ɑ-KG to 2-hydroxyglutarate (2HG), resulting in a hypermethylation phenotype. WT, wild type.

Fig. 3 |. Histone H3 methylation modifications and disruption in cancer.

a, Histone H3 methyltransferases and demethylases. Mutations to genes in bold are implicated in cancer. b, Depiction of MLL–ENL-rearranged leukaemia. The MLL CXXC domain targets the fusion protein to MLL target sites and the ENL domain recruits DOT1L methyltransferase activity, resulting in aberrant methylation. c, Schematic of oncohistone mutations in cancer and their antagonism with methyltransferases. d, The H3K36M mutation results in the global reduction of H3K36me3 levels, whereas the H3K34 mutation diminishes only cis-H3K36me3 levels. e, Schematic of H3K27M and H3K36M oncohistone chromatin occupancy compared to wild-type (WT) histone H3. H3K27M inhibits H3K27me3, resulting in RNA polymerase II (RNA Pol II) recruitment and activation, as assessed by H3K27ac levels. The H3K36M mutation reduces genome-wide H3K36me2/3 and H3K27me3 levels. DIPG, diffuse intrapontine glioma.

Fig. 4 |. CRCs in cancer: a focus on mSWI/SNF (BAF) complexes.

a, Cartoon depiction of the chromatin remodelling activities: nucleosome sliding, ejection and placement, and histone variant exchange. b, Domain organization within the ATPase subunit of each class of CRCs. c, Pan-cancer mutation frequency across chromatin remodelling families. Mutation frequencies for all genes encoding members of each family were summed and represented as a heatmap. Analysis of public The Cancer Genome Atlas (TCGA) data for 33 available cancer types showing mutation frequency rates across 4 CRC families and SWI/SNF-like ATRX/DAXX. d, mSWI/SNF subcomplex protein associations overlayed with subunit-specific mutations identified across cancer types. The mSWI/SNF subcomplex-defining subunits are coloured in red (BAF), purple (PBAF) and green (ncBAF). e, mSWI/SNF complexes are typically associated with active chromatin landscapes and directly oppose Polycomb-mediated repression. f, Gain-of-function perturbations to mSWI/SNF complexes include fusion oncoproteins and transcription factors (TFs) that tether to mSWI/SNF complex surfaces. The SS18–SSX fusion oncoprotein replaces the SS18 subunit to hijack complexes genome wide, the EWS–FLI1 (friend leukaemia integration 1 transcription factor) fusion directs complexes to GGAA repeat sites in Ewing sarcoma and the ERG transcription factor targets BAF complexes to ETS DNA sequence motifs genome wide, each of which results in aberrant, cancer-specific transcriptional regulation. ACTB, actin, cytoplasmic 1; ACTL6, actin-like protein 6; BCL7, B-cell CLL/lymphoma 7 protein family member; CHD, chromodomain helicase DNA-binding; DPF, zinc-finger protein neuro-d4; GLTSCR1, BRD4-interacting CRC-associated protein; HELICc, helicase superfamily C-terminal; HSA, helicase/SANT associated; PCL, Polycomb-like protein; PHF10, PHD finger protein 10; SLIDE, SANT-like but with several insertions; T-ALL, T cell acute lymphoblastic leukaemia; TMPRSS2, transmembrane protease serine 2.