Biology subjects

Berletch, J.

Publications and source records attributed to Berletch, J..

3 recordsLinked to original sources

bioRxiv2026

Cell-type specific allelic dampening of sex-linked genes in sex chromosome aneuploidy

Common sex chromosome aneuploidies (SCAs) often present with cognitive and cardiovascular dysfunction in humans. To address SCA effects on gene expression and DNA methylation in relevant cell types, we differentiated neural precursor cells (NPCs) and cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) with different numbers of sex chromosomes, including isogenic and independent lines. As expected, the expression of genes that escape X inactivation (escapees) mostly increases with the number of inactive X chromosomes (Xi). However, allelic analysis shows dampening of escapees specifically on the Xi in XXY compared to XX in both NPCs and CMs, revealing a novel type of dosage compensation in SCA. In contrast, Y-linked gene expression is higher in XXY versus XY NPCs, but the opposite is observed in CMs. This may explain the greater number of differentially expressed autosomal genes in NPCs versus CMs with an added Y chromosome, while effects of added X chromosomes are similar between cell types. Concordantly, changes in autosomal DNA methylation are mainly driven by the presence of a Y chromosome. These findings highlight the cell-type specificity of sex-linked and autosomal gene regulation in SCA conditions. HighlightsO_LISex chromosome aneuploidy induces cell-type specific changes in gene expression C_LIO_LIDampening of the inactive X chromosome in XXY alleviate X overexpression C_LIO_LIHigh Y-linked gene expression in XXY neuronal precursor cells but not cardiomyocytes C_LIO_LISex chromosome aneuploidy disrupts sex biases in autosomal gene expression C_LI

molecular biology↗

bioRxiv2020

Allele-specific gene regulation by KDM6A

KDM6A demethylates the repressive histone mark H3K27me3 and thus plays an important role in developmental gene regulation. KDM6A expression is female-biased due to escape from X inactivation, suggesting that this protein may play a role in sex differences. Here, we report that maternal and paternal alleles of a subset of mouse genes are differentially regulated by KDM6A. Knockouts of Kdm6a in male and female embryonic stem cells derived from F1 hybrid mice from reciprocal interspecific crosses resulted in preferential downregulation of maternal alleles of a number of genes implicated in development. Moreover, the majority of these genes exhibited a maternal allele expression bias, which was observed in both reciprocal crosses. Promoters of genes downregulated on maternal but not paternal alleles demonstrated a loss of chromatin accessibility, while the expected increase in H3K27me3 levels occurred only at promoters of genes downregulated on paternal but not maternal alleles. These results illustrate parent-of-origin mechanisms of gene regulation by KDM6A, consistent with histone demethylation-dependent and -independent activities.

molecular biology↗

bioRxiv2017

Orientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome

The mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts separated by a boundary or hinge region. Using in situ DNase Hi-C in mouse cells with deletions or inversions within the hinge we show that the conserved repeat locus Dxz4 alone is sufficient to maintain the bipartite structure and that Dxz4 orientation controls the distribution of long-range contacts on the Xi. Frequent long-range contacts between Dxz4 and the telomeric superdomain are either lost after its deletion or shifted to the centromeric superdomain after its inversion. This massive reversal in contact distribution is consistent with the reversal of CTCF motif orientation at Dxz4. De-condensation of the Xi after Dxz4 deletion is associated with partial restoration of TADs normally attenuated on the Xi. There is also an increase in chromatin accessibility and CTCF binding on the Xi after Dxz4 deletion or inversion, but few changes in gene expression, in accordance with multiple epigenetic mechanisms ensuring X silencing. We propose that Dxz4 represents a structural platform for frequent long-range contacts with multiple loci in a direction dictated by the orientation of a bank of CTCF motifs at Dxz4, which may work as a ratchet to form the distinctive bipartite structure of the condensed Xi.

molecular biology↗