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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [RNA-seq]

ABSTRACT: Mammalian sex is determined by a network of antagonistic genes that are well characterized. However, its non-coding regulation is still largely unknown. Here we explore the 3D chromatin landscape of sex determination in vivo. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis approach that identifies 3D regulatory hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, which deletion results in male-to-female sex reversal.

ORGANISM(S): Mus musculus

PROVIDER: GSE217617 | GEO | 2022/11/21

REPOSITORIES: GEO

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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [Hi-C]

Project description:Mammalian sex is determined by a network of antagonistic genes that are well characterized. However, its non-coding regulation is still largely unknown. Here we explore the 3D chromatin landscape of sex determination in vivo. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis approach that identifies 3D regulatory hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, which deletion results in male-to-female sex reversal.

2022-11-21 | GSE217616 | GEO

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Project description:Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

| PRJNA899827 | ENA

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [RNA-seq]

Project description:Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [RNA-seq]

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Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [Hi-C]

Project description:Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis [Hi-C]

| PRJNA899840 | ENA

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-21 | GSE217618 | GEO

Temporal auto-regulation during PU.1 locus SubTAD formation (4C-seq)

Project description:Epigenetic control of gene expression occurs through discrete spatial chromosomal units called topologically associating domains (TADs), but the exact spatial requirements of most genes are unknown; this is of particular interest for genes involved in disease. We therefore applied high-resolution chromosomal conformation capture-sequencing to map the three-dimensional (3D) organization of the locus encoding the key myeloid transcription factor PU.1 in healthy monocytes and acute myeloid leukemia (AML) cells. We identified a dynamic ~75kb unit (SubTAD) as the genomic region in which spatial interactions between PU.1 gene regulatory elements occur during myeloid differentiation and are interrupted in AML. Within this SubTAD, initiating the spatial chromosomal interactions requires PU.1 auto-regulation and recruitment of the chromatin-adaptor protein LDB1 (LIM domain-binding protein 1). However, once formed, this SubTAD remains stable even when auto-regulation is impaired. Thus, our data support that PU.1 auto-regulation functions in a ‘hit-and-run’ manner, whereby it organizes chromosomal loops to create a transcriptionally active chromatin architecture.

2018-10-15 | GSE110683 | GEO

Transcriptome Differences between Alternative Sex Determining Genotypes in the House Fly, Musca domestica

Project description:Sex determination evolves rapidly, often because of turnover of the genes at the top of the pathway. The house fly, Musca domestica, has a multifactorial sex determination system, allowing us to identify the selective forces responsible for the evolutionary turnover of sex determination in action. There is a male determining factor, M, on the Y chromosome (Y^M), which is probably the ancestral state. An M factor on the third chromosome (III^M) has reached high frequencies in multiple populations across the world, but the evolutionary forces responsible for the invasion of III^M are not resolved. To test if the III^M chromosome invaded because of sex-specific selection pressures, we used mRNA sequencing to determine if isogenic males that differ only in the presence of the Y^M or III^M chromosome have different gene expression profiles. We find that more genes are differentially expressed between Y^M and III^M males in testis than head, and that genes with male-biased expression are most likely to be differentially expressed between Y^M and III^M males. This suggests that male phenotypes, especially those related to male fertility, are more likely to be affected by the male-determining chromosome, supporting the hypothesis that sex-specific selection acts on alleles linked to the male-determining locus driving evolutionary turnover in the sex determination pathway. We additionally find that III^M males have a "masculinization" gene expression profile, suggesting that the III^M chromosome has accumulated an excess of male-beneficial alleles because of its male-limited transmission.

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Basic helix-loop-helix transcription factor Tcf21 is downstream target of male sex-determining gene SRY

Project description:The cascade of molecular events involved in mammalian sex determination has been shown to involve the SRY gene, but specific downstream events have eluded researchers for decades. The current study identifies one of the first direct downstream targets of the male sex-determining factor SRY as the basic-helix-loop-helix (bHLH) transcription factor TCF21. SRY was found to directly associate with the Tcf21 promoter SRY/SOX9 response element both in vitro and in vivo during male sex determination. TCF21 was found to promote an in vitro sex reversal of embryonic ovarian cells to promote precursor Sertoli cell differentiation. Therefore, SRY acts directly on the Tcf21 promoter to, in part, initiate a cascade of events associated with Sertoli cell differentiation and embryonic testis development.

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The male determining M-factor of the global disease vector Musca domestica is a paralog of the generic splice factor CWC22

Project description:Sex determination mechanisms are bewilderingly diverse. A cascade of genes with hierarchical regulation characterizes sex determination pathways in insects. How such pathways evolve is poorly understood, partly due to a lack of comparative data. Houseflies are well known for their polymorphic sex determination with populations carrying a dominant male determiner M on the Y chromosome or any of the five autosomes. We identified the male determining gene Mdm responsible for splicing regulation of the key switch transformer by exploiting the existence of housefly populations with different sex determination mechanisms. We demonstrate that Mdm originated from duplication of CWC22/nucampholin, a generic and essential splicing regulator across Metazoans with a crucial role in exon-junction complex assembly and non-sense mediated decay. We show that strains with the M-locus on the Y and on different autosomes carry multiple copies of Mdm indicating that the same male determiner translocated to different genomic sites in the genome. We found that embryonic RNAi-based silencing of Mdm leads to differentiation of ovaries in males, while targeted Mdm disruption with CRISPR/CAS-9 resulted in complete sex reversal to fertile females. Our study reveals how a duplicate of a gene with a general splice-regulation role during development can be recruited to serve a specific function in the determination of male sex. Mdm appears to be unique to the housefly representing a compelling example for the plasticity at the instructive level of sex determination hierarchies.

2017-05-12 | E-MTAB-5080 | biostudies-arrayexpress

Temporal auto-regulation during PU.1 locus SubTAD formation (ChIP-seq)

Project description:Epigenetic control of gene expression occurs within discrete spatial chromosomal units called topologically associating domains (TADs), but the exact spatial requirements of most genes are unknown; this is of particular interest for genes involved in cancer. We therefore applied high-resolution chromosomal conformation capture-sequencing to map the three-dimensional (3D) organization of the human locus encoding the key myeloid transcription factor PU.1 in healthy monocytes and acute myeloid leukemia (AML) cells. We identified a dynamic ~75kb unit (SubTAD) as the genomic region in which spatial interactions between PU.1 gene regulatory elements occur during myeloid differentiation and are interrupted in AML. Within this SubTAD, proper initiation of the spatial chromosomal interactions requires PU.1 autoregulation and recruitment of the chromatin-adaptor protein LDB1 (LIM domain-binding protein 1). However, once these spatial interactions have occurred, LDB1 stabilizes them independently of PU.1 auto-regulation. Thus, our data support that PU.1 auto-regulates its expression in a ‘hit-and-run’ manner by initiating stable chromosomal loops that result in a transcriptionally active chromatin architecture.

2018-10-15 | GSE120142 | GEO

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