Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes

Hung, Stevephen; Saiakhova, Alina; Faber, Zachary J; Bartels, Cynthia F.; Neu, Devin; Bayles, Ian; Ojo, Evelyn; Hong, Ellen S.; Pontius, William; Morton, Andrew; Liu, Ruifu; Kalady, Matthew F.; Wald, David N.; Markowitz, Sanford D.; Scacheri, Peter C.

doi:10.7554/elife.40760

Cited by 24 publications

(23 citation statements)

References 41 publications

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“…The observed negative correlation between GC content and mutation rate was consistent with other observations of lower mutation rate in GC rich regions 23,[39][40][41][42] and mechanistically with both GC biased gene conversion 43 and lower rates of cytosine deamination in GC rich regions 10,[44][45][46][47] . Furthermore, the histone modifications H3K4me1 and H3K27ac are known to be associated with lower mutation rates, particularly in active genes 21,[48][49][50] , and several studies have revealed explicit connections between H3K36me3 and DNA mismatch repair 13,16,17 . These chromatin marks were enriched in gene bodies (Fig.…”

Section: Classical Evolutionary Theory Maintains That Mutation Rate Vmentioning

confidence: 99%

Mutation bias shapes gene evolution inArabidopsis thaliana

Monroe

Srikant

Carbonell‐Bejerano

et al. 2020

Preprint

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Classical evolutionary theory maintains that mutation rate variation between genes should be random with respect to fitness 1-4 and evolutionary optimization of genic mutation rates remains controversial 3,5 . However, it has now become known that cytogenetic (DNA sequence + epigenomic) features influence local mutation probabilities 6 , which is predicted by more recent theory to be a prerequisite for beneficial mutation rates between different classes of genes to readily evolve 7 . To test this possibility, we used de novo mutations in Arabidopsis thaliana to create a high resolution predictive model of mutation rates as a function of cytogenetic features across the genome . As expected, mutation rates are significantly predicted by features such as GC content, histone modifications, and chromatin accessibility. Deeper analyses of predicted mutation rates reveal effects of introns and untranslated exon regions in distancing coding sequences from mutational hotspots at the start and end of transcribed regions in A. thaliana . Finally, predicted coding region mutation rates are significantly lower in genes where mutations are more likely to be deleterious, supported by numerous estimates of evolutionary and functional constraint. These findings contradict neutral expectations that mutation probabilities are independent of fitness consequences. Instead they are consistent with the evolution of lower mutation rates in functionally constrained loci due to cytogenetic features, with important implications for evolutionary biology 8 .Monroe et al. Genome-wide mutation bias in A. thalianaA core maxim of evolutionary biology, codified through experiments completed in the early 1940s 1 , is that the "consequences of a mutation have no influence whatsoever on the probability that this mutation will or will not occur." 2 This assertion has profound implications for understanding organismal evolution and predicting human disease. That genic mutation rates might have been optimized during evolution has been extensively challenged with a strong argument: selection for mutation rates on a gene-by-gene basis cannot overcome the barrier of genetic drift 3 . And while reports of non-random relationships between mutation rates and fitness consequences have been previously made, these have been questioned because they have largely relied on substitution rates in natural populations rather than direct measures of de novo mutations 3,9-12 .More recently though, discoveries in genome biology have inspired a reevaluation of classical theories of mutation rate evolution. It is now recognized that mutation rates across genomes are influenced by DNA sequence composition, epigenomic features, and bias in the targets of DNA repair mechanisms 5,6,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . It is also known that broad classes of genes (e.g., housekeeping genes) exist in distinct cytogenetic (DNA sequence + epigenomic) states. This provides an opportunity for mutation rates to evolve in beneficial directi...

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Section: Classical Evolutionary Theory Maintains That Mutation Rate Vmentioning

confidence: 99%

Mutation bias shapes gene evolution inArabidopsis thaliana

Monroe

Srikant

Carbonell‐Bejerano

et al. 2020

Preprint

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“…To this end, utilization of the WGS technology and integration of mutational data with transcriptomic and epigenomic maps have been a proven path to not only identify noncoding mutations but also attribute them with potential biological functions. Various studies have determined functional noncoding mutations with low frequency by integrating mutations with transcriptomes and epigenomes (15,28,32,40). These successes encourage comprehensive characterization of tumors using a compendium of high-throughput assays.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

“…Notably, the highly mutated ER-binding sites are associated with more frequent chromatin loop contacts (ChIA-PET and Hi-C data), and the associated distal genes are expressed at a higher level. Recently, Hung and colleagues (40) revealed that indels with the mismatch repair (MMR) signature led to allelebiased enhancer activation and selection of enhancers in microsatellite instable colorectal cancer. These studies highlight that noncoding mutations induced by a certain mutational process may function collectively.…”

Section: Understanding Functional Roles Of Noncoding Mutationsmentioning

confidence: 99%

“…However, this method does not capture the endogenous genomic features such as epigenetic states and 3D chromosome structures and for many enhancers, the gene target is not known. The advances in the CRISPR-based tools are expected to provide great flexibility and robustness to interrogate the regulatory impacts of noncoding mutations in an endogenous genomic context (15,(40)(41)(42)(43). CRISPR tools can be used to perform gene expression regulation, epigenome editing, live-cell chromatin imaging, and manipulation of chromatin topology (41).…”

Section: Understanding Functional Roles Of Noncoding Mutationsmentioning

confidence: 99%

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Mapping and Making Sense of Noncoding Mutations in the Genome

Yang¹,

Adli²

2019

Cancer Research

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Whole-genome sequencing efforts of tumors and normal tissues have identified numerous genetic mutations, both somatic and germline, that do not overlap with coding genomic sequences. Attributing a functional role to these noncoding mutations and characterizing them using experimental methods has been more challenging compared with coding mutations. In this review, we provide a brief introduction to the world of noncoding mutations. We discuss recent progress in identifying noncoding mutations and the analytic and experimental approaches utilized to interpret their functional roles. We also highlight the potential mechanisms by which a noncoding mutation may exert its effect and discuss future challenges and opportunities.

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“…The current literature on alterations of enhancer elements in CRC is scarce, with only a handful of studies(11-13) with small sample sizes that profiled primary tumors. Furthermore, a comprehensive understanding of other chromatin state alterations and their functional contribution to tumor progression is mostly lacking.…”

Section: Introductionmentioning

confidence: 99%

Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer

Orouji

Raman

Singh

et al. 2020

Preprint

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The extent and function of chromatin state aberrations during colorectal cancer (CRC) progression is not completely understood. Here, by comprehensive epigenomic characterization of 56 tumors, adenomas, and their matched normal tissues, we define the dynamics of chromatin states during the progression of colorectal cancer. H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumor-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was crucial for excessive proliferation. Consistently, combination of MEK plus bromodomain (BET) inhibition was found to have synergistic effects in CRC patient-derived xenograft (PDX) models. Probing inter-tumor heterogeneity, we identified four distinct enhancer subtypes (EpiC), three of which correlate well with previously defined transcriptomic subtypes (CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, and TGFBi) for three EPIC groups. Our data suggest that the dynamics of active enhancer underlies colorectal cancer progression and the patient-specific active enhancer patterns govern their unique gene expression patterns which can be leveraged for precision combination therapy.

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Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes

Cited by 24 publications

References 41 publications

Mutation bias shapes gene evolution inArabidopsis thaliana

Mutation bias shapes gene evolution inArabidopsis thaliana

Mapping and Making Sense of Noncoding Mutations in the Genome

Chromatin State Dynamics Confers Specific Therapeutic Strategies in Enhancer Subtypes of Colorectal Cancer

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