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A hypermethylation strategy utilized by enhancer-bound CARM1 to promote estrogen receptor a-dependent transcriptional activation and breast carcinogenesis (RNA-seq)

ABSTRACT: While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their roles in carcinogenesis, particularly in estrogen receptor alpha (ERa)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) due to its high expression and the associated poor prognosis in ERa-positive breast cancers. We first uncovered the chromatin-binding landscape and transcriptional targets of CARM1 in the presence of estrogen in ERa-positive breast cancer cells employing genomic and transcriptomics approaches. CARM1 was found to be predominantly and specifically recruited to ERa-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced gene transcriptional activation in response to estrogen. Global mapping of CARM1 substrates revealed that CARM1 methylates a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor signaling, chromatin organization, chromatin remodeling and others. Intriguingly, a number of proteins were hypermethylated exclusively by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor domain-containing 3 (TDRD3), to ensure the full activation of estrogen/ERa target genes. In consistent with its critical role in estrogen-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERa-positive breast cancer cells in vitro and tumor growth in mice. Taken together, our study uncovered a “hypermethylation” strategy utilized by CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124447 | GEO | 2020/01/17

REPOSITORIES: GEO

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Project description:Multiple signaling pathways ultimately modulate the epigenetic information embedded in the chromatin of gene promoters by recruiting epigenetic enzymes. We found that, in estrogen-regulated gene programming, the acetyltransferase CREB-binding protein (CBP) is specifically and exclusively methylated by the coactivator-associated arginine methyltransferase (CARM1) in vivo. CARM1-dependent CBP methylation and p160 coactivators were required for estrogen-induced recruitment to chromatin targets. Notably, methylation increased the histone acetyltransferase (HAT) activity of CBP and stimulated its autoacetylation. Comparative genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) studies revealed a variety of patterns by which p160, CBP, and methyl-CBP (meCBP) are recruited (or not) by estrogen to chromatin targets. Moreover, significant target gene-specific variation in the recruitment of (1) the p160 RAC3 protein, (2) the fraction of a given meCBP species within the total CBP, and (3) the relative recruitment of different meCBP species suggests the existence of a target gene-specific âfingerprintâ for coregulator recruitment. Crossing ChIP-seq and transcriptomics profiles revealed the existence of meCBP âhubsâ within the network of estrogen-regulated genes. Together, our data provide evidence for an unprecedented mechanism by which CARM1-dependent CBP methylation results in gene-selective association of estrogen-recruited meCBP species with different HAT activities and specifies distinct target gene hubs, thus diversifying estrogen receptor programming. Examination of estrogen-induced binding site in H3396 cells under Estrogen (E2) or Ethanol (EtOH) treatment: CBP in E2; CBP in EtOH (two technical replicate); CBPR742m in E2 (two technical replicates); CBPR768m in E2; CBPR768m in EtOH; CBPR2151m in E2; CBPR2151m in EtOH; Estrogen receptor alpha (ERa) in E2; ERa in EtOH; Total Histone 3 and 4 acetylated in E2; H3K18ac in E2; H3K18ac in EtOH; Polymerase II (PolII) in E2; PolII in EtOH; RAC3 in E2; Input DNA sample in E2

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A hypermethylation strategy utilized by enhancer-bound CARM1 to promote estrogen receptor a-dependent transcriptional activation and breast carcinogenesis (RNA-seq)

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