Characterization of a genomic region 8 kb downstream of GFI1B associated with myeloproliferative neoplasms
A genomic locus 8 kb downstream of the transcription factor GFI1B (Growth Factor Independence 1B) predisposes to clonal hematopoiesis and myeloproliferative neoplasms. One of the most significantly associated polymorphisms in this region is rs621940-G. GFI1B auto-represses GFI1B, and altered GFI1B e...
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Veröffentlicht in: | Biochimica et biophysica acta. Molecular basis of disease 2021-12, Vol.1867 (12), p.166259-166259, Article 166259 |
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Zusammenfassung: | A genomic locus 8 kb downstream of the transcription factor GFI1B (Growth Factor Independence 1B) predisposes to clonal hematopoiesis and myeloproliferative neoplasms. One of the most significantly associated polymorphisms in this region is rs621940-G. GFI1B auto-represses GFI1B, and altered GFI1B expression contributes to myeloid neoplasms. We studied whether rs621940-G affects GFI1B expression and growth of immature cells. GFI1B ChIP-seq showed clear binding to the rs621940 locus. Preferential binding of various hematopoietic transcription factors to either the rs621940-C or -G allele was observed, but GFI1B showed no preference. In gene reporter assays the rs621940 region inhibited GFI1B promoter activity with the G-allele having less suppressive effects compared to the C-allele. However, CRISPR-Cas9 mediated deletion of the locus in K562 cells did not alter GFI1B expression nor auto-repression. In healthy peripheral blood mononuclear cells GFI1B expression did not differ consistently between the rs621940 alleles. Long range and targeted deep sequencing did not detect consistent effects of rs621940-G on allelic GFI1B expression either. Finally, we observed that myeloid colony formation was not significantly affected by either rs621940 allele in 193 healthy donors. Together, these findings show no evidence that rs621940 or its locus affect GFI1B expression, auto-repression or growth of immature myeloid cells.
•A genomic locus surrounding rs621940 associates with myeloproliferative neoplasms.•GFI1B binds to the genomic region 8 kb downstream of GFI1B adjacent to rs621940.•Removal of the genomic region does not affect GFI1B expression levels.•GFI1B expression is not significantly affected by either rs621940 allele.•Clonogenic growth of myeloid progenitors is not affected by rs621940 in 193 donors. |
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ISSN: | 0925-4439 1879-260X |
DOI: | 10.1016/j.bbadis.2021.166259 |