title: Opposing functions of H2BK120 ubiquitylation and H3K79 methylation in the regulation of pluripotency by the Paf1 complex.
abstract: Maintenance of stem cell plasticity is determined by the ability to balance opposing forces that control gene expression. Regulation of transcriptional networks, signaling cues and chromatin-modifying mechanisms constitute crucial determinants of tissue equilibrium. Histone modifications can affect chromatin compaction, therefore co-transcriptional events that influence their deposition determine the propensities toward quiescence, self-renewal, or cell specification. The Paf1 complex (Paf1C) is a critical regulator of RNA PolII elongation that controls gene expression and deposition of histone modifications, however few studies have focused on its role affecting stem cell fate decisions. Here we delineate the functions of Paf1C in pluripotency and characterize its impact in deposition of H2B ubiquitylation (H2BK120-ub) and H3K79 methylation (H3K79me), 2 fundamental histone marks that shape transcriptional regulation. We identify that H2BK120-ub is increased in the absence of Paf1C on its embryonic stem cell targets, in sharp contrast to H3K79me, suggesting opposite functions in the maintenance of self-renewal. Furthermore, we found that core pluripotency genes are characterized by a dual gain of H2BK120-ub and loss of H3K79me on their gene bodies. Our findings elucidate molecular mechanisms of cellular adaptation and reveal novel functions of Paf1C in the regulation of the self-renewal network.
authors.affiliation: a Department of Pathology , NYU School of Medicine , New York , NY , USA.|b Laura & Isaac Perlmutter Cancer Center , NYU School of Medicine , New York , NY , USA.|c Helen L. & Martin S. Kimmel Center for Stem Cell Biology , NYU School of Medicine , New York , NY , USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Strikoudis
authors.affiliation: a Department of Pathology , NYU School of Medicine , New York , NY , USA.|b Laura & Isaac Perlmutter Cancer Center , NYU School of Medicine , New York , NY , USA.|c Helen L. & Martin S. Kimmel Center for Stem Cell Biology , NYU School of Medicine , New York , NY , USA.
authors.forename: Charalampos
authors.identifier: 0000-0002-7345-8288
authors.initials: C
authors.lastname: Lazaris
authors.affiliation: d Department of Biochemistry and Molecular Genetics , Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University , Chicago , IL , USA.
authors.forename: Panagiotis
authors.identifier: 0000-0001-6374-8954
authors.initials: P
authors.lastname: Ntziachristos
authors.affiliation: a Department of Pathology , NYU School of Medicine , New York , NY , USA.|b Laura & Isaac Perlmutter Cancer Center , NYU School of Medicine , New York , NY , USA.|e Applied Bioinformatics Laboratories, Office of Science & Research , NYU School of Medicine , NY , USA.
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: a Department of Pathology , NYU School of Medicine , New York , NY , USA.|b Laura & Isaac Perlmutter Cancer Center , NYU School of Medicine , New York , NY , USA.|c Helen L. & Martin S. Kimmel Center for Stem Cell Biology , NYU School of Medicine , New York , NY , USA.
authors.forename: Iannis
authors.identifier: 0000-0001-6857-1035
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000066673:Cell Self Renewal; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins; D006657:Histones / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D000066450:Mouse Embryonic Stem Cells; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C459458:Phf5a protein, mouse; C547921:RNA polymerase II associated factor 1, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D015534:Trans-Activators
keywords: Elongation; Embryonic stem cells; Paf1 complex; Phf5a; Pluripotency; Promoter-proximal pausing; RNA Polymerase II; Self-renewal network