title: Methylation specifies distinct estrogen-induced binding site repertoires of CBP to chromatin.
abstract: 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 "fingerprint" for coregulator recruitment. Crossing ChIP-seq and transcriptomics profiles revealed the existence of meCBP "hubs" 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.
authors.affiliation: Department of Cancer Biology, Institut Génétique de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch-Cedex, France.
authors.forename: Danilo Guillermo
authors.initials: DG
authors.lastname: Ceschin
authors.forename: Mannu
authors.initials: M
authors.lastname: Walia
authors.forename: Sandra Simone
authors.initials: SS
authors.lastname: Wenk
authors.forename: Carine
authors.initials: C
authors.lastname: Duboé
authors.forename: Claudine
authors.initials: C
authors.lastname: Gaudon
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiao
authors.forename: Lucas
authors.initials: L
authors.lastname: Fauquier
authors.forename: Martial
authors.initials: M
authors.lastname: Sankar
authors.forename: Laurence
authors.initials: L
authors.lastname: Vandel
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D003067:Coenzymes / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D016678:Genome / Q000235:genetics; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011485:Protein Binding / Q000187:drug effects; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism
chemical_list: D002843:Chromatin; D003067:Coenzymes; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases