Abstract
Hematopoietic stem cells (HSCs) provide life-long production of blood cells and undergo self-renewal division in order to sustain the stem cell pool. Precisely regulated HSC pool maintenance and blood cell production is vital for organismal survival. We have identified a protein, latexin (Lxn), as a novel regulator of HSCs in mice, whose natural variation in the expression is inversely correlated with HSC population size. However, the molecular mechanisms involved in transcriptional regulation of Lxn in HSCs have not been clearly defined, and the genetic factors contributing to its natural variation are unknown. Here we report that an upstream regulatory sequence of the Lxn gene controls the promoter activity, and histone protein H2A.X interacts with the promoter and acts as a transcriptional activator. We identify a functional single nucleotide polymorphism (SNP), rs31528793, in the Lxn promoter that is associated with the differential binding of H2A.X, as identified by mass spectrometry. SNP rs31528793 attenuates the ability of H2A.X to bind and activate the Lxn promoter, as shown by chromatin immunoprecipitation and promoter luciferase assay. Moreover, overexpression of H2A.X increases the endogenous Lxn level and decreases HSC number and self-renewal. Concomitant blockage of Lxn activation significantly reverses these phenotypic changes, suggesting Lxn is one of the downstream targets and functional mediators of H2A.X. This study, for the first time, reveal the regulatory mechanism involved in Lxn transcription and uncover the functional role of naturally occurring genetic variants in determining differential gene expression and phenotypic diversity in HSC population. Disclosures No relevant conflicts of interest to declare.
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