CBX2-dependent transcriptional landscape: implications for human sex development and its defects

Abstract

Sex development, a complex and indispensable process in all vertebrates, has still not been completely elucidated, although new genes involved in sex development are constantly being discovered and characterized. Chromobox Homolog 2 (CBX2) is one of these new additions and has been identified through a 46,XY girl with double heterozygous variants on CBX2.1, causing Differences of Sex Development (DSD). The mutated CBX2.1 failed to adequately regulate downstream targets important for sex development in humans, specifically steroidogenic factor 1 (NR5A1/SF1). To better place CBX2.1 in the human sex developmental cascade, we performed siRNA and CBX2.1 overexpression experiments and created a complete CRISPR/Cas9-CBX2 knockout in Sertoli-like cells. Furthermore, we deployed Next Generation Sequencing techniques, RNA-Sequencing and DamID-Sequencing, to identify new potential CBX2.1 downstream genes. The combination of these two next generation techniques enabled us to identify genes that are both bound and regulated by CBX2.1. This allowed us not only to expand our current knowledge about the influence of CBX2.1 in human sex development, but also to advance our insight in the mechanisms governing one of the most important decisions during embryonal development, the commitment to either female or male gonads.

Defective monocyte plasticity and altered cAMP pathway characterize USB1‐mutated poikiloderma with neutropenia Clericuzio type

“…Alterations in some of these genes could be associated with the diverse clinical manifestations in PN patients, such as lower expression of CBX2, SEMA3A and NEURL3 with hypogonadism [37][38][39] and lower expression of transcription factor GATA2 and regulatory gene CEBPZOS with leukopenia/ monocytopenia as in MonoMAC syndrome. 40,41 Differentiation of monocytes from haematopoietic progenitor cells involves several transcription factors, including GATA2, IRF8, KLF4 and Spl1.…”

<b><i>CBX2</i></b> in DSD: The Quirky Kid on the Block

“…Later, the CBX2.1 and CBX2.2 transcriptional landscape was further expanded through protein/DNA interaction studies of CBX2 binding partners, coupled with in vitro functional analysis of downstream gene targets in human pre-granulosa (KGN) and Sertoli-like cells (NT2/ D1), adding to the repertoire of CBX2-regulated factors [Bouazzi et al, 2019;Sproll et al, 2019]. The selected genes and their respective role during development or association with DSD is summarized in Table 1.…”

Cbx2, a PcG Family Gene, Plays a Regulatory Role in Medaka Gonadal Development

“…Previous reports suggested that CBX2, a member of PcG, was an epigenetically modified transcriptional repressor. Recently, it was also found to serve as a transcriptional activator to regulate the expression of downstream genes [12,13]. However, the functional role of cbx2 in gonadal development is still unclear in vertebrates other than mammals.…”