When Down Is Up: Heterochromatin, Nuclear Organization and X Upregulation

Makki, Reem; Meller, Victoria H.

doi:10.3390/cells10123416

Cited by 8 publications

(3 citation statements)

References 160 publications

(198 reference statements)

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“…In summary, the work here does not support the widely held view [21,34,[104][105][106] that H3K36me3 is essential for Drosophila MSL complex spreading. Our transcriptomic study of X-gene regulation in Set2, H3.2 K36 , H3.3 K36 and combined H3 K36 mutants of both sexes is inconsistent with this idea.…”

Section: Discussioncontrasting

confidence: 99%

Set2 and H3K36 regulate theDrosophilamale X chromosome in a context-specific manner, independent from MSL complex spreading

Salzler,

Vandadi,

Matera

2024

Preprint

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Dosage compensation in Drosophila involves upregulating male X-genes two-fold. This process is carried out by the MSL (male-specific lethal) complex, which binds high-affinity sites and spreads to surrounding genes. Current models of MSL spreading focus on interactions of MSL3 (male-specific lethal 3) with histone marks; in particular, Set2-dependent H3 lysine-36 trimethylation (H3K36me3). However, Set2 might affect DC via another target, or there could be redundancy between canonical H3.2 and variant H3.3 histones. Further, it is difficult to parse male-specific effects from those that are simply X-specific. To discriminate among these possibilities, we employed genomic approaches in H3K36 residue and Set2 writer mutants. The results confirm a role for Set2 in X-gene regulation, but show that expression trends in males are often mirrored in females. Instead of global, male-specific reduction of X-genes in Set2/H3K36 mutants, we observe heterogeneous effects. Interestingly, we identified cohorts of genes whose expression was significantly altered following loss of H3K36 or Set2, but changes were in opposite directions, suggesting that H3K36me states have reciprocal functions. In contrast to H4K16R controls, analysis of combined H3.2K36R/H3.3K36R mutants neither showed consistent reduction in X-gene expression, nor any correlation with MSL3 binding. Examination of other developmental stages/tissues revealed additional layers of context-dependence. Our studies implicate BEAF-32 and other insulator proteins in Set2/H3K36-dependent regulation. Overall, the data are inconsistent with the prevailing model wherein H3K36me3 directly recruits the MSL complex. We propose that Set2 and H3K36 support DC indirectly, via processes that are utilized by MSL but common to both sexes.

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Section: Discussioncontrasting

confidence: 99%

Set2 and H3K36 regulate theDrosophilamale X chromosome in a context-specific manner, independent from MSL complex spreading

Salzler,

Vandadi,

Matera

2024

Preprint

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“…In one model, the size of the DGDE for genes within a newly acquired DNA-loss will be underestimated because of the transcripts of the same genes inherited from the euploid precursor cell. However, in an alternative model, dosage compensation may also lead to milder DGDEs for DNA losses 112 through increased expression of genes on the remaining chromosome, similar to the increase of transcription of genes on the single X chromosome in male D. melanogaster 113, 114 or in mouse embryonic stem cells with monosomy X 115 . Our findings are possibly concordant with such a mechanism since the fold-change in expression of genes in regions with DNA-losses is only ∼0.8 instead of the expected 0.5.…”

Section: Discussionmentioning

confidence: 99%

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Gallardo

Sifrim

Chappell

et al. 2023

Preprint

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The frequent acquisition of genomic abnormalities in human preimplantation embryos is a leading cause of pregnancy loss, but does not necessarily prohibit healthy offspring. However, the impact of genomic abnormalities on cellular states and development of the early human embryo remains largely unclear. Here, we characterise aneuploidy and reconstruct gene regulatory networks in human preimplantation embryos, and investigate gene expression and developmental perturbations instigated by aneuploidy using single-cell genome-and-transcriptome sequencing (G&T-seq). At the genomic level, we show that acquired numerical and structural chromosomal aberrations are frequent across all stages of early embryogenesis and in all cell lineages. At the transcriptome level, we identify regulators of cell identity and uncover a network of 248 transcription factors from 10 major gene regulatory modules that characterise the distinct lineages of human preimplantation embryos. By integrating single-cell DNA- with RNA-information, we unveil how expression levels are affected by losses or gains of the corresponding genes in embryonic cells across human preimplantation development, as well as how copy-number aberrant transcription factor genes perturb the expression of their cognate target genes in euploid regions. Furthermore, we reveal a majority of aneuploid cells show a developmental delay and reduced fitness, indicating cell competition within the mosaic diploid-aneuploid embryo, which may contribute to selection against aneuploid cells and the birth of healthy offspring from mosaic diploid-aneuploid embryos. In summary, our multi-modal analyses provide unprecedented insights into early human embryo development.

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“…These chromatin modifications, possibly mediated by Mof, may serve to dampen variance in X-linked gene expression in both sexes, and therefore reduce differential expression on the X chromosome. Furthermore, there is a complex interplay between heterochromatin and dosage compensation in Drosophila ( Makki and Meller 2021 ), which could also contribute to a variance dampening effect in both sexes.…”

Section: Discussionmentioning

confidence: 99%

Induction and inhibition of Drosophila X chromosome gene expression are both impeded by the dosage compensation complex

Meisel

Asgari

Schlamp

et al. 2022

G3 Genes|Genomes|Genetics

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Sex chromosomes frequently differ from the autosomes in the frequencies of genes with sexually dimorphic or tissue-specific expression. Multiple hypotheses have been put forth to explain the unique gene content of the X chromosome, including selection against male-beneficial X-linked alleles, expression limits imposed by the haploid dosage of the X in males, and interference by the dosage compensation complex (DCC) on expression in males. Here, we investigate these hypotheses by examining differential gene expression in Drosophila melanogaster following several treatments that have widespread transcriptomic effects: bacterial infection, viral infection, and abiotic stress. We found that genes that are induced (up-regulated) by these biotic and abiotic treatments are frequently under-represented on the X chromosome, but so are those that are repressed (down-regulated) following treatment. We further show that whether a gene is bound by the DCC in males can largely explain the paucity of both up- and down-regulated genes on the X chromosome. Specifically, genes that are bound by the DCC, or close to a DCC high-affinity site, are unlikely to be up- or down-regulated after treatment. This relationship, however, could partially be explained by a correlation between differential expression and breadth of expression across tissues. Nonetheless, our results suggest that DCC binding, or the associated chromatin modifications, inhibit both up- and down-regulation of X chromosome gene expression within specific contexts, including tissue-specific expression. We propose multiple possible mechanisms of action for the effect, including a role of Males absent on the first (Mof), a component of the DCC, as a dampener of gene expression variance in both males and females. This effect could explain why the Drosophila X chromosome is depauperate in genes with tissue-specific or induced expression, while the mammalian X has an excess of genes with tissue-specific expression.

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When Down Is Up: Heterochromatin, Nuclear Organization and X Upregulation

Cited by 8 publications

References 160 publications

Set2 and H3K36 regulate theDrosophilamale X chromosome in a context-specific manner, independent from MSL complex spreading

Set2 and H3K36 regulate theDrosophilamale X chromosome in a context-specific manner, independent from MSL complex spreading

A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

Induction and inhibition of Drosophila X chromosome gene expression are both impeded by the dosage compensation complex

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