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Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome.

Libertini E, Lebreton A, Lakisic G, Dillies MA, Beck S, Coppée JY, Cossart P, Bierne H - Front Genet (2015)

Bottom Line: We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX).We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains.Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome.

View Article: PubMed Central - PubMed

Affiliation: Plate-forme Transcriptome et Epigénome, Département Génomes et Génétique, Institut Pasteur Paris, France ; Medical Genomics Group, UCL Cancer Institute, University College London London, UK.

ABSTRACT
BAH domain-containing protein 1 (BAHD1) is involved in heterochromatin formation and gene repression in human cells. BAHD1 also localizes to the inactive X chromosome (Xi), but the functional significance of this targeting is unknown. So far, research on this protein has been hampered by its low endogenous abundance and its role in epigenetic regulation remains poorly explored. In this work, we used whole-genome bisulfite sequencing (BS-seq) to compare the DNA methylation profile of HEK293 cells expressing low levels of BAHD1 (HEK-CT) to that of isogenic cells stably overexpressing BAHD1 (HEK-BAHD1). We show that increasing BAHD1 levels induces de novo DNA methylation on autosomes and a marked hypomethylation on the X chromosome (chrX). We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX). Autosomal BAHD1-DMRs were predominantly hypermethylated and located to satellites, interspersed repeats, and intergenic regions. In contrast, BAHD1-DMRs on chrX were mainly hypomethylated and located to gene bodies and enhancers. We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains. Half of these "BAHD1-Associated differentially methylated Domains" (BADs) overlapped with lamina-associated domains (LADs). Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome.

No MeSH data available.


Related in: MedlinePlus

Relationship between BAHD1-DMRs and gene expression. Histograms represent, for each autosome and chrX, the number (“counts”) of hypermethylated or hypomethylated DMRs that are located within a window of 10 kb upstream to 10 kb downstream of a gene differentially expressed (activated or repressed) in HEK-BAHD1 cells compared to HEK-CT.
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Figure 3: Relationship between BAHD1-DMRs and gene expression. Histograms represent, for each autosome and chrX, the number (“counts”) of hypermethylated or hypomethylated DMRs that are located within a window of 10 kb upstream to 10 kb downstream of a gene differentially expressed (activated or repressed) in HEK-BAHD1 cells compared to HEK-CT.

Mentions: With the aim of investigating the potential association between BAHD1-induced DNA methylation changes and gene expression, we generated transcriptome datasets of HEK-CT and HEK-BAHD1 lines, using Affymetrix DNA arrays. Analysis of differential gene expression between the two lines yielded 1304 up-regulated and 1137 down-regulated transcripts upon BAHD1 overexpression (LPE, BH-adjusted p < 0.05). Given the role of BAHD1 in transcriptional repression, our analysis principally focused on genes that were down-regulated in HEK-BAHD1 cells. We found BAHD1-specific DMRs in 701 (61%) repressed genes, within a window encompassing 10 kb upstream to 10 kb downstream of each gene. In most autosomes, there was a significantly higher proportion of hyper-DMRs than hypo-DMRs associated with repressed genes (Figure 3), suggesting that BAHD1-associated de novo DNA methylation on autosomes is mainly associated with gene repression.


Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome.

Libertini E, Lebreton A, Lakisic G, Dillies MA, Beck S, Coppée JY, Cossart P, Bierne H - Front Genet (2015)

Relationship between BAHD1-DMRs and gene expression. Histograms represent, for each autosome and chrX, the number (“counts”) of hypermethylated or hypomethylated DMRs that are located within a window of 10 kb upstream to 10 kb downstream of a gene differentially expressed (activated or repressed) in HEK-BAHD1 cells compared to HEK-CT.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664705&req=5

Figure 3: Relationship between BAHD1-DMRs and gene expression. Histograms represent, for each autosome and chrX, the number (“counts”) of hypermethylated or hypomethylated DMRs that are located within a window of 10 kb upstream to 10 kb downstream of a gene differentially expressed (activated or repressed) in HEK-BAHD1 cells compared to HEK-CT.
Mentions: With the aim of investigating the potential association between BAHD1-induced DNA methylation changes and gene expression, we generated transcriptome datasets of HEK-CT and HEK-BAHD1 lines, using Affymetrix DNA arrays. Analysis of differential gene expression between the two lines yielded 1304 up-regulated and 1137 down-regulated transcripts upon BAHD1 overexpression (LPE, BH-adjusted p < 0.05). Given the role of BAHD1 in transcriptional repression, our analysis principally focused on genes that were down-regulated in HEK-BAHD1 cells. We found BAHD1-specific DMRs in 701 (61%) repressed genes, within a window encompassing 10 kb upstream to 10 kb downstream of each gene. In most autosomes, there was a significantly higher proportion of hyper-DMRs than hypo-DMRs associated with repressed genes (Figure 3), suggesting that BAHD1-associated de novo DNA methylation on autosomes is mainly associated with gene repression.

Bottom Line: We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX).We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains.Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome.

View Article: PubMed Central - PubMed

Affiliation: Plate-forme Transcriptome et Epigénome, Département Génomes et Génétique, Institut Pasteur Paris, France ; Medical Genomics Group, UCL Cancer Institute, University College London London, UK.

ABSTRACT
BAH domain-containing protein 1 (BAHD1) is involved in heterochromatin formation and gene repression in human cells. BAHD1 also localizes to the inactive X chromosome (Xi), but the functional significance of this targeting is unknown. So far, research on this protein has been hampered by its low endogenous abundance and its role in epigenetic regulation remains poorly explored. In this work, we used whole-genome bisulfite sequencing (BS-seq) to compare the DNA methylation profile of HEK293 cells expressing low levels of BAHD1 (HEK-CT) to that of isogenic cells stably overexpressing BAHD1 (HEK-BAHD1). We show that increasing BAHD1 levels induces de novo DNA methylation on autosomes and a marked hypomethylation on the X chromosome (chrX). We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX). Autosomal BAHD1-DMRs were predominantly hypermethylated and located to satellites, interspersed repeats, and intergenic regions. In contrast, BAHD1-DMRs on chrX were mainly hypomethylated and located to gene bodies and enhancers. We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains. Half of these "BAHD1-Associated differentially methylated Domains" (BADs) overlapped with lamina-associated domains (LADs). Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome.

No MeSH data available.


Related in: MedlinePlus