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The DAXX co-repressor is directly recruited to active regulatory elements genome-wide to regulate autophagy programs in a model of human prostate cancer

ABSTRACT: The DAXX co-repressor is directly recruited to active regulatory elements genome-wide to regulate autophagy programs in a model of human prostate cancer

PROVIDER: PRJNA283304 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2013842.fastq.gz	Fastqsanger.gz
	SRR2013433.fastq.gz	Fastqsanger.gz
	SRR2013843.fastq.gz	Fastqsanger.gz
	SRR2013434.fastq.gz	Fastqsanger.gz
	SRR2013844.fastq.gz	Fastqsanger.gz

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Project description:Objective: Daxx is a protein with multiple functions and is essential for embryonic development. Daxx knockout embryos fail to develop properly and exhibit lethal phenotype around E6.5. One of the important functions is as a histone chaperone for the histone H3 variant, H3.3. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres and repeat loci. Here, we investigated how histone chaperone function of Daxx contributes to the embryonic development. Methods: We developed two Daxx mutant alleles in the mouse germline which abolish the interactions between Daxx and Atrx (DaxxY130A), Daxx and H3.3 (DaxxS226A). We set up mating between either heterozygous DaxxY130A or heterozygous DaxxS226A individually and looked for the viability of homozygous mutants at different development stages. We also performed bulk RNA-seq on tissues from the two mutant embryos and analyzed the changes in gene expression and transposable elements (TE). Results: We found that the interaction between Daxx and Atrx is dispensable for viability in both the pre- and post-natal setting as homozygous Daxx-Y130A mutants are both viable and fertile. The loss of the Atrx interaction, however, does cause dysregulated expression of both endogenous retroviruses and nearby protein coding genes. On the contrary, the interaction between Daxx and H3.3 is not required for embryonic development but is essential for postnatal viability. Transcriptome analysis of embryonic tissues demonstrates that this interaction is important for silencing endogenous retroviruses and for maintaining proper hematopoiesis. Conclusions: The histone chaperone function of Daxx is dispensable for embryonic development but important for hematopoiesis, which is independent of the interaction with Atrx. Moreover, both the interactions with Atrx and with H3.3 is important for regulation of ERV expression. Overall, these results clearly demonstrate that Daxx and H3.3 have both Atrx-dependent and independent functions, advancing our understanding of this epigenetic regulatory complex.

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The DAXX co-repressor is directly recruited to active regulatory elements genome-wide to regulate autophagy programs in a model of human prostate cancer

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