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Mosaic loss of chromosome Y leads to clonal hematopoiesis and promotes leukemogenesis in mice

ABSTRACT: Mosaic loss of chromosome Y (mLOY) is the most frequent chromosome alternation in the blood cells of aging adult male and is closely associated with AML, so we designed experiments to explore the mechanism. Bulk RNA sequencing was performed with AML1-ETO;sgSsty2/sgScramble;Trp53-/- Bone Marrow in vivo and sgSsty2/sgSsty1/sgScramble;Trp53-/- c-kit+ HSPCs in vitro. And our study demonstrates that mLOY is a functional driver for clonal hematopoiesis and leukemogenesis. KDM5D, a gene mediated H3K4 demethylation and located on both human and mouse chromosome Y, we wondered whether KDM5D could be a critical gene responsible for the pathology of mLOY. So bulk RNA sequencing was performed with sgKdm5d/sgScramble;Trp53-/- Bone marrow in vivo and Trp53-/- c-kit+ HSPCs in vitro to explore the mechanism of Kdm5d in mLOY.

ORGANISM(S): Mus musculus

PROVIDER: GSE165208 | GEO | 2022/01/19

REPOSITORIES: GEO

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Project description:The objective of Human Y Chromosome Proteome Project is to map and annotate all proteins encoded by genes on the MSY sequences. Lysine (K)-specific demethylase 5D (KDM5D) is located on the AZFb region of Y chromosome and encode for a JmjC-domain-containing protein. Changes in KDM5D transcript level in prostate cancer have shown in various studies. To investigation the function of KDM5D in prostate cancer, we knocked down the expression of KDM5D in human prostate cancer cell (DU-145) using siRNA approach. Down-regulation of KDM5D was confirmed by qRT-PCR and western-blot analyses. Cell cycle analysis and MTS assay revealed that down-regulation of KDM5D induces cell proliferation. Furthermore, we observed that KDM5D down-regulation could effectively decrease apoptosis, as measured by the propidium iodide flow cytometric assay. To further our study, we investigated the dynamic of KDM5D protein network using shotgun label free quantitative proteomics approach in knockdown and control cell line. In summary, 102 down-regulated and 107 up-regulated proteins were detected from 894 total proteins. Up-regulated proteins mainly activated ribosome biogenesis whereas down-regulated genes were mainly involved in proteolysis, cell death and metabolic process. The result raw files were converted to mzXML format and processed through the global proteome machine (GPM) software (version 2.1.1) of the X!Tandem algorithm (freely available at http://www.thegpm.org). The 16 gel fractions were processed serially for each experiment and the output files were generated as non-redundant, merged files with protein identifications with log (e) values less than -1, for each individual gel fraction. A protein database compiled from NCBI (Homo sapien) was used in GPM to search the tandem mass spectra; the database also included common trypsin and human peptide contaminants. False discovery rates (FDR) were evaluated by searching against a reversed sequence database. Search parameters included MS and MS/MS tolerances of +2 Da and +0.2 Da, carbamidomethylation of cysteine as fixed modifications, oxidation of methionine as variable modifications and tolerance of two missed tryptic cleavages and K/R-P cleavages.

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Mosaic loss of chromosome Y leads to clonal hematopoiesis and promotes leukemogenesis in mice

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