title: Inactivation or non-reactivation: what accounts better for the silence of sex chromosomes during mammalian male meiosis?
abstract: During the first meiotic prophase in male mammals, sex chromosomes undergo a program of transcriptional silencing called meiotic sex chromosome inactivation (MSCI). MSCI is triggered by accumulation of proteins like BRCA1, ATR, and γH2AX on unsynapsed chromosomes, followed by local changes on the sex chromatin, including histone modifications, incorporation of specific histone variants, non-histone proteins, and RNAs. It is generally thought that MSCI represents the transition of unsynapsed chromatin from a transcriptionally active state to a repressed state. However, transcription is generally low in the whole nucleus during the early stages of the first meiotic prophase, when markers of MSCI first appear, and is then reactivated globally during pachytene. Thus, an alternative possibility is that MSCI represents the targeted maintenance and/or reinforcement of a prior repressed state, i.e., a failure to reactivate. Here, we present an analysis of the temporal and spatial appearance of transcriptional and MSCI markers, as well as chromatin modifications related to transcriptional regulation. We show that levels of RNA pol II and histone H3 acetylated at lysine 9 (H3K9ac) are low during leptotene, zygotene, and early pachytene, but increase strongly in mid-pachytene, indicating that reactivation occurs with some delay after synapsis. However, while transcription markers appear abundantly on the autosomes at mid-pachytene, they are not directed to the sex chromosomes. Interestingly, we found that chromatin modifications related to transcriptional silencing and/or MSCI, namely, histone H3 trimethylated at lysine 9 (H3K9me3), histone H3 monomethylated at lysine 4 (H3K4me1), γH2AX, SUMO1, and XMR, appear on the sex chromosomes before autosomes become reactivated. These results suggest that the onset of MSCI during late zygotene and early pachytene may prevent sex chromosome reactivation during mid-pachytene instead of promoting inactivation de novo. Additionally, we found temporal differences between the X and Y chromosomes in the recruitment of DNA repair and MSCI markers, indicating a differential regulation of these processes. We propose that many of the meiotic defects attributed to failure to silence sex chromosomes could be interpreted as a more general process of transcriptional misregulation that occurs under certain pathological circumstances in zygotene and early pachytene.
authors.affiliation: Unidad de Biología Celular, Departamento de Biología, Universidad Autónoma de Madrid, Madrid, Spain. jesus.page@uam.es
authors.forename: Jesús
authors.initials: J
authors.lastname: Page
authors.forename: Roberto
authors.initials: R
authors.lastname: de la Fuente
authors.forename: Marcia
authors.initials: M
authors.lastname: Manterola
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Parra
authors.forename: Alberto
authors.initials: A
authors.lastname: Viera
authors.forename: Soledad
authors.initials: S
authors.lastname: Berríos
authors.forename: Raúl
authors.initials: R
authors.lastname: Fernández-Donoso
authors.forename: Julio S
authors.initials: JS
authors.lastname: Rufas
mesh_terms: D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin / Q000378:metabolism; D023902:Chromosome Pairing / Q000502:physiology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D008297:Male; D049469:Meiotic Prophase I / Q000235:genetics*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D049471:Pachytene Stage / Q000502:physiology; D012319:RNA Polymerase II / Q000378:metabolism; D016601:RNA-Binding Proteins; D025842:SUMO-1 Protein / Q000378:metabolism; D014158:Transcription, Genetic; D014960:X Chromosome / Q000378:metabolism*; D014998:Y Chromosome / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C106710:Rad51ap1 protein, mouse; D025842:SUMO-1 Protein; C489754:Sycp1 protein, mouse; C490062:Sycp3 protein, mouse; C475961:gamma-H2AX protein, mouse; D012319:RNA Polymerase II