MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction

Loss of MYSM1 inhibits the oncogenic activity of cMYC in B cell lymphoma

“… 9 We recently conducted the first genome‐wide analysis of MYSM1‐regulated genes and demonstrated that in primary murine haematopoietic stem and progenitor cells MYSM1 promotes the expression of many genes encoding ribosomal proteins and translation factors. 10 Interestingly, MYSM1 was previously shown to interact with cMYC in B1a lymphocytes 11 ; however, the role of MYSM1 as a transcriptional regulator in haematologic malignancies remains unexplored. As cMYC is the major transcriptional regulator for the genes encoding the ribosomal and translational machinery, here we investigate the cross‐talk between MYSM1 and cMYC in the regulation of these gene‐sets and its implications for cMYC‐driven carcinogenesis.…”

“…To compare the location of the genomic binding sites of MYSM1 and cMYC, we consolidated the ChIP‐Seq datasets for cMYC and its dimerization partner MAX from multipotent haematopoietic progenitor cells HPC7 12 , 13 with the MYSM1 ChIP‐Seq acquired in our recent work in a B cell progenitor cell line Ba/F3. 10 This identified 45 binding sites shared by MYSM1 and cMYC (Figure 1A‐B ), all located within 1kb to the nearest gene transcription start site (TSS, Table S1 ). Importantly, 28 of these shared binding sites localized near the genes encoding ribosomal proteins (RPs) and 4 others near the genes encoding translation factors (Figure 1C‐D , Table S1 ).…”

“… Co‐localization of MYSM1 and cMYC DNA‐binding sites at the promoters of genes encoding ribosomal proteins ( RPs ). A, Consolidation of genome‐wide DNA‐binding data for MYSM1, cMYC and MAX using ChIP‐seq datasets from Belle et al, JCI Insight 2020 (MYSM1) 10 and Wilson et.al., Blood 2016 (cMYC, MAX), 13 highlighting 45 shared binding sites between MYSM1 and cMYC/MAX. Input and IgG served as background controls for the two cell lines.…”

“…D, Genomic snapshots of cMYC and MYSM1 binding near select RP gene promoters. Data for MYSM1 are from Belle et al, JCI Insight 2020 10 ; data for cMYC are from Wilson et.al., Blood 2016. 13 E, Validation of cMYC binding at known MYSM1 DNA‐binding sites at the promoters of genes encoding ribosomal proteins and translation factors, in a B cell precursor cell line Ba/F3 using ChIP‐qPCR.…”

“…We have previously validated MYSM1 binding to the promoters of RP genes in Ba/F3 cells by ChIP‐qPCR, and also demonstrated a reduction in RP ‐gene expression in Mysm1 ‐shRNA knockdown Ba/F3 cells and in Mysm1 ‐deficient primary haematopoietic stem and progenitor cells. 10 To further validate the overlap in the genomic binding sites of MYSM1 and cMYC in Ba/F3 cells, the binding of cMYC at the MYSM1‐binding sites of select genes encoding RPs and translation factors was tested and confirmed with ChIP‐qPCR (Figure 1E , Supporting Information S1 ). The binding of MYSM1 and cMYC at the shared sites was also confirmed in cells derived from EuMyc mouse B cell lymphoma, 14 , 15 specifically for the Rpl7 and Eef1g gene promoters (data not shown).…”