Abstract
Despite sharing the same sequence specificity in vitro and in vivo, CCCTC-binding factor (CTCF) and its paralog brother of the regulator of imprinted sites (BORIS) are simultaneously expressed in germ cells. Recently, ChIP-seq analysis revealed two classes of CTCF/BORIS-bound regions: single CTCF target sites (1xCTSes) that are bound by CTCF alone (CTCF-only) or double CTCF target sites (2xCTSes) simultaneously bound by CTCF and BORIS (CTCF&BORIS) or BORIS alone (BORIS-only) in germ cells and in BORIS-positive somatic cancer cells. BORIS-bound regions (CTCF&BORIS and BORIS-only sites) are, on average, enriched for RNA polymerase II (RNAPII) binding and histone retention in mature spermatozoa relative to CTCF-only sites, but little else is known about them. We show that subsets of CTCF&BORIS and BORIS-only sites are occupied by several testis-specific transcriptional regulators (TSTRs) and associated with highly expressed germ cell-specific genes and histone retention in mature spermatozoa. We also demonstrate a physical interaction between BORIS and one of the analyzed TSTRs, TATA-binding protein (TBP)-associated factor 7-like (TAF7L). Our data suggest that CTCF and BORIS cooperate with additional TSTRs to regulate gene expression in developing male gametes and histone retention in mature spermatozoa, potentially priming certain regions of the genome for rapid activation following fertilization.
Highlights
CTCF is a ubiquitously expressed chromatin-binding factor that contains 11 zinc fingers (ZFs) and is conserved from Drosophila to human[1,2]
These transcriptional regulators (TSTRs)-occupied CTCF&brother of the regulator of imprinted sites (BORIS) (TSTR-CTCF&BORIS) and BORIS-only sites (TSTR-BORIS-only sites) are associated with genes highly expressed in testis and involved in male germ cell development
We found that substantial fractions of CTCF&BORIS and BORIS-only sites are occupied by transcriptional regulator (TR) with known roles in male gametogenesis and associated with genes highly expressed in testis as well as sites of histone retention in spermatozoa
Summary
CTCF is a ubiquitously expressed chromatin-binding factor that contains 11 zinc fingers (ZFs) and is conserved from Drosophila to human[1,2]. CTCF&BORIS and BORIS-only sites were associated with histone retention in mature spermatozoa, which has been proposed to be a consequence of active transcription in spermatids[33] and is associated with genes expressed in early zygotic development[33,34,35,36,37]. We find that TSTR-associated BORIS-bound sites, but not their counterparts not bound by TSTRs, are associated with histone retention in mature sperm Together, these observations suggest a functional link between CTCF and BORIS and other testis-specific TSTRs in the regulation of germ cell transcription. Our analyses provide a refined view of BORIS-bound sites, identifying subsets of sites potentially involved in testis transcription and suggesting novel avenues for the exploration of functional connections between CTCF, BORIS, and several TSTRs in the regulation of male gametogenesis
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