SET domain‐containing protein 5 is required for expression of primordial germ cell specification‐associated genes in murine embryonic stem cells

Abstract

Primordial germ cell (PGC) specification is one of the most fundamental processes in developmental biology. Because PGCs are a common source of both gametes, generation of PGCs from embryonic stem cells (ESCs) is a useful model for analysing the germ line lineage. Although several studies focused on the role of epigenetic regulation on PGC differentiation from ESCs in vitro have been published, germ line commitment remains poorly understood. Here, we show that SET domain-containing protein (Setd5), which has a previously unknown function, is essential for regulating germ cell-associated genes in murine ESCs (mESCs). Even though Setd5 knockdown with 3 distinct shRNAs did not affect expression of pluripotency genes or levels of global histone methylation, all 3 shRNAs significantly diminished the expression of early and late-stage PGC-associated genes. Furthermore, our immunoprecipitation assay showed that Setd5 can interact with Tbl1xr1 and Ctr9, which are components of 2 different transcriptional regulatory complexes, namely, NcoR1 corepressor complex and Paf1 complex, respectively, in mESCs. Taken together, our data suggest that Setd5 is required for maintaining PGC-associated genes and Setd5-associated protein complexes containing Tbl1xr1 and Ctr9, which in turn are likely involved in regulating germ cell-related genes in mESCs.

SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring

“…However, it has been proposed that SETD5 regulates chromatin accessibility at promoter regions by stimulating histone deacetylase (HDAC) activity, as described for its putative orthologs Set3p and UpSET (Deliu et al, 2018;Osipovich et al, 2016;Rincó n-Arano et al, 2012). Homozygous deletion of Setd5 in mice is lethal at an early embryonic stage due to cardiovascular defects (Osipovich et al, 2016), while its downregulation in embryonic stem cells (ESCs) leads to alterations in myogenic, vasculogenic, and primordial germ cell lineage differentiation (Osipovich et al, 2016;Yu et al, 2017). Few studies are reported on SETD5 molecular function during neural development and maturation and how its inactivation may lead to ID/ASD.…”

Genetic variations on SETD5 underlying autistic conditions

“…Current findings on SETD5 activity postulates that by interacting with the polymerase‐associated factor 1 complex (PAF1C) and the nuclear receptor co‐repressor (N‐CoR), SETD5 may be involved in chromatin accessibility during transcription (Kim et al, ; Rincon‐Arano et al, ; Osipovich et al, ; Yu et al, ).…”

Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes

“…Methyltransferase activity has also not been detected for the SETD5 paralog MLL5 ( Madan et al, 2009 ; Mas-y-Mas et al, 2016 ) or for SETD5 orthologs including yeast Set3p ( Pijnappel et al, 2001 ) and Drosophila UpSET ( Rincon-Arano et al, 2012 ), suggesting that, if SETD5 indeed possesses such catalytic activity, it was acquired during the process of evolution. Proteomics analyses by several research groups have consistently identified components of two complexes—the HDAC3 and PAF1 complexes—among proteins found to associate with SETD5 ( Osipovich et al, 2016 ; Yu et al, 2017 ; Deliu et al, 2018 ; Nakagawa et al, 2020 ; Wang et al, 2020 ; Matsumura et al, 2021 ). The HDAC3 complex functions mainly as a transcriptional repressor by catalyzing deacetylation of histone proteins ( Seto and Yoshida, 2014 ), whereas the PAF1 complex regulates transcription by modulating promoter-proximal pausing, transcriptional elongation and termination, and RNA 3′-end formation by RNA polymerase II ( Branden Van Oss et al, 2017 ).…”