Dataset Information

An androgen signaling axis uses a writer and a reader of ADP-ribosylation to control protein complex assembly

ABSTRACT: Androgen signaling through the androgen receptor (AR) regulates multiple pathways in both normal and prostate cancer cells. Androgen regulates diverse aspects of the AR life cycle, including its post-translational modification, but understanding how specific modifications influence AR activity has been mostly elusive. Here, we show that androgen regulates AR through a pathway mediated by the mono-ADP ribosyltransferase, Parp7. We show that Parp7 ADP-ribosylates AR on multiple cysteines, and that a subset of these sites mediates agonist-specific recruitment of the E3 ligase Dtx3L/Parp9. Tandem macrodomains in Parp9 selectively recognize ADP ribosylated AR, and Dtx3L/Parp9 affects expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by 60 Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of a new androgen signaling axis that uses a writer and reader of ADP-ribosylation to modulate AR activity.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: JJ Park

LAB HEAD: Bryce M. Paschal

PROVIDER: PXD018811 | Pride | 2021-05-28

REPOSITORIES: Pride

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Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly.

Yang Chun-Song CS Jividen Kasey K Kamata Teddy T Dworak Natalia N Oostdyk Luke L Remlein Bartlomiej B Pourfarjam Yasin Y Kim In-Kwon IK Du Kang-Ping KP Abbas Tarek T Sherman Nicholas E NE Wotton David D Paschal Bryce M BM

Nature communications 20210511 1

Androgen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ...[more]

PMID: 33976187

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Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Mnase sensitivity of sperm DNA, indicating nucleosomal, not protamine, packaging was altered in mice by manipulating poly(ADP-ribose) metabolism in adult males using a specific PARP inhibitor for 6 weeks. Abnormal sperm nucleosomal organization of males analyzed by these tiling arrays was compared with differential gene expression in 2 cell embryos fathered by these males analyzed by separate gene expression arrays and RNA sequencing.

			Action	DRS
	Sampledescription.xlsx	Xlsx
	pR-AR_Chymotrypsin_PTM.sf3	Other
	pR-AR_GluC_PTM.sf3	Other
	pR-AR_Trypsin_PTM.sf3	Other
	q190508q02.raw	Raw