title: Replication-dependent histone genes are actively transcribed in differentiating and aging retinal neurons.
abstract: In the mammalian genome, each histone family contains multiple replication-dependent paralogs, which are found in clusters where their transcription is thought to be coupled to the cell cycle. Here, we wanted to interrogate the transcriptional regulation of these paralogs during retinal development and aging. We employed deep sequencing, quantitative PCR, in situ hybridization (ISH), and microarray analysis, which revealed that replication-dependent histone genes were not only transcribed in progenitor cells but also in differentiating neurons. Specifically, by ISH analysis we found that different histone genes were actively transcribed in a subset of neurons between postnatal day 7 and 14. Interestingly, within a histone family, not all paralogs were transcribed at the same level during retinal development. For example, expression of Hist1h1b was higher embryonically, while that of Hist1h1c was higher postnatally. Finally, expression of replication-dependent histone genes was also observed in the aging retina. Moreover, transcription of replication-dependent histones was independent of rapamycin-mediated mTOR pathway inactivation. Overall, our data suggest the existence of variant nucleosomes produced by the differential expression of the replication-dependent histone genes across retinal development. Also, the expression of a subset of replication-dependent histone isotypes in senescent neurons warrants re-examining these genes as "replication-dependent." Thus, our findings underscore the importance of understanding the transcriptional regulation of replication-dependent histone genes in the maintenance and functioning of neurons.
authors.affiliation: a Department of Physiology and Neurobiology ; University of Connecticut ; Storrs , CT USA.
authors.forename: Abdul Rouf
authors.initials: AR
authors.lastname: Banday
authors.forename: Marybeth
authors.initials: M
authors.lastname: Baumgartner
authors.forename: Sahar
authors.initials: S
authors.lastname: Al Seesi
authors.forename: Devi Krishna Priya
authors.initials: DK
authors.lastname: Karunakaran
authors.forename: Aditya
authors.initials: A
authors.lastname: Venkatesh
authors.forename: Sean
authors.initials: S
authors.lastname: Congdon
authors.forename: Christopher
authors.initials: C
authors.lastname: Lemoine
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Kilcollins
authors.forename: Ion
authors.initials: I
authors.lastname: Mandoiu
authors.forename: Claudio
authors.initials: C
authors.lastname: Punzo
authors.forename: Rahul N
authors.initials: RN
authors.lastname: Kanadia
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000235:genetics*; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055495:Neurogenesis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000502:physiology; D055351:Retinal Neurons / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D019927:Cyclin E; D006657:Histones; D020033:Protein Isoforms; D012333:RNA, Messenger; D019938:Cyclin D1; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: AA; CE; Chr; GCL; INL; ISH; NE; ONBL; ONL; PCR; RPE; amino acid; chromosome; cytoplasmic extract; development; expression; ganglion cell layer; histones; in situ hybridization; inner nuclear layer; isotypes; nuclear extract; outer neuroblastic layer; outer nuclear layer; polymerase chain reaction; qPCR; quantitative PCR; replication-dependent; retina; retinal pigment epithelium; transcription; variant nucleosome