Latexin regulation by HMGB2 is required for hematopoietic stem cell maintenance

Abstract

regulation by HMGB2 is required for hematopoietic stem cell maintenance. ABSTRACTHematopoietic stem cells provide life-long production of blood cells and undergo selfrenewal division in order to sustain the stem cell pool. Homeostatic maintenance of hematopoietic stem cell pool and blood cell production is vital for organismal survival. We previously reported that latexin is a negative regulator of hematopoietic stem cells in mice, whose natural variation in the expression is inversely correlated with hematopoietic stem cell number. However, the molecular mechanisms regulating latexin transcription remain largely unknown, and the genetic factors contributing to its natural variation are not clearly defined.Here we discovered a chromatin protein, high-mobility group protein B2, as a novel transcriptional suppressor of latexin by using DNA pull-down and mass spectrometry. Highmobility group protein B2 knockdown increases latexin expression at transcript and protein levels, and decreases hematopoietic stem cell number and regeneration capacity in vivo. Concomitant blockage of latexin activation significantly reverses these phenotypic changes,suggesting that latexin is one of the downstream targets and functional mediators of highmobility group protein B2. We further identified a functional single nucleotide polymorphism, rs31528793, in the latexin promoter that binds to high-mobility group protein B2 and affects the promoter activity. G allelic variation in rs31528793 associates with the higher latexin expression and lower hematopoietic stem cell number, whereas C allele indicates the lower latexin expression and higher stem cell number. This study, for the first time, reveal that latexin transcription is regulated by both trans-acting (high-mobility group protein B2) and cis-acting (single nucleotide polymorphism rs31528793) factors. It uncovers the functional role of naturally occurring genetic variants, in combination with epigenetic regulator, in determining differential gene expression and phenotypic diversity in hematopoietic stem cell population.

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Genetic fingerprint defines hematopoietic stem cell pool size and function

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“…[4][5][6][7] These developments are enabling detailed characterization of normal and disordered human erythropoiesis. [8][9][10][11][12][13] Importantly, as a result of this progress it is now possible to obtain insights into at what stage of the complex process of erythroid differentiation various genes contribute to ineffective erythropoiesis.…”

“…In this issue of Haematologica, the same group who published the above-mentioned paper, 10 Zhang et al identified the promoter region of the Lxn gene that controls the level of Lxn gene expression via both HMGB2, a chromatin protein, and genetic variations in the promoter region. 11 To study the transcriptional regulation of Lxn, the authors characterized the upstream region of the Lxn gene. Based on the natural variation of Lxn expression, they searched SNP with CpG island and identified a region with strong promoter activity in the upstream.…”

Cellular heterogeneity landscape in laryngeal squamous cell carcinoma

“…HMGB2 is ubiquitous and ample in eukaryotic cells, and regulating proliferation serve as its primary function. HMGB2 could regulate latexin to keep hematopoietic stem cell proliferation and differentiation 55 . In articular cartilage, loss of HMGB2 reduces the regeneration capacity of mesenchymal stem cells by increasing apoptosis 56 .…”