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

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: GSE217616 | GEO | 2022/11/21

REPOSITORIES: GEO

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

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.

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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

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

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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

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

2022-11-21 | GSE217618 | GEO

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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.

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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.

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