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Distinct dosage compensations of ploidy-sensitive and -insensitive X chromosome genes during development and in diseases.

ABSTRACT: The active X chromosome in mammals is upregulated to balance its dosage to autosomes during evolution. However, it is elusive why the known dosage compensation machinery showed uneven and small influence on X genes. Here, based on >20,000 transcriptomes, we identified two X gene groups (ploidy-sensitive [PSX] and ploidy-insensitive [PIX]), showing distinct but evolutionarily conserved dosage compensations (termed XAR). We demonstrated that XAR-PIX was downregulated whereas XAR-PSX upregulated at both RNA and protein levels across cancer types, in contrast with their trends during stem cell differentiation. XAR-PIX, but not XAR-PSX, was lower and correlated with autoantibodies and inflammation in patients of lupus, suggesting that insufficient dosage of PIX genes contribute to lupus pathogenesis. We further identified and experimentally validated two XAR regulators, TP53 and ATRX. Collectively, we provided insights into X dosage compensation in mammals and demonstrated different regulation of PSX and PIX and their pathophysiological roles in human diseases.

SUBMITTER: Guo M

PROVIDER: S-EPMC9926305 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Distinct dosage compensations of ploidy-sensitive and -insensitive X chromosome genes during development and in diseases.

Guo Mengbiao M Fang Zhengwen Z Chen Bohong B Songyang Zhou Z Xiong Yuanyan Y

iScience 20230118 2

The active X chromosome in mammals is upregulated to balance its dosage to autosomes during evolution. However, it is elusive why the known dosage compensation machinery showed uneven and small influence on X genes. Here, based on >20,000 transcriptomes, we identified two X gene groups (ploidy-sensitive [PSX] and ploidy-insensitive [PIX]), showing distinct but evolutionarily conserved dosage compensations (termed XAR). We demonstrated that XAR-PIX was downregulated whereas XAR-PSX upregulated at ...[more]

PMID: 36798435

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Project description:BackgroundCHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development.MethodsTo examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate.ResultsMild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice.ConclusionsTogether, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.

Project description:Copy number changes in protein-coding genes are detrimental if the consequent changes in protein concentrations disrupt essential cellular functions. The dosage sensitivity of transcription factor (TF) genes is particularly interesting because their products are essential in regulating the expression of genetic information. From four recently curated data sets of dosage-sensitive genes (genes with conserved copy numbers across mammals, ohnologs, and two data sets of haploinsufficient genes), we compiled a data set of the most reliable dosage-sensitive (MRDS) genes and a data set of the most reliable dosage-insensitive (MRDIS) genes. The MRDS genes were those present in all four data sets, while the MRDIS genes were those absent from any one of the four data sets and with the probability of being loss of function-intolerant (pLI) values < 0.5 in both of the haploinsufficient gene data sets. Enrichment analysis of TF genes among the MRDS and MRDIS gene data sets showed that TF genes are more likely to be dosage-sensitive than other genes in the human genome. The nuclear receptor family was the most enriched TF family among the dosage-sensitive genes. TF families with very few members were also deemed more likely to be dosage-sensitive than TF families with more members. In addition, we found a certain number of dosage-insensitive TFs. The most typical were the Krüppel-associated box domain-containing zinc-finger proteins (KZFPs). Gene ontology (GO) enrichment analysis showed that the MRDS TFs were enriched for many more terms than the MRDIS TFs; however, the proteins interacting with these two groups of TFs did not show such sharp differences. Furthermore, we found that the MRDIS KZFPs were not significantly enriched for any GO terms, whereas their interacting proteins were significantly enriched for thousands of GO terms. Further characterizations revealed significant differences between MRDS TFs and MRDIS TFs in the lengths and nucleotide compositions of DNA-binding sites as well as in expression level, protein size, and selective force.

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Distinct dosage compensations of ploidy-sensitive and -insensitive X chromosome genes during development and in diseases.

Publications

Distinct dosage compensations of ploidy-sensitive and -insensitive X chromosome genes during development and in diseases.

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