Page 59 - Haematologica March 2020

Hematopoiesis
Latexin regulation by HMGB2 is required for hematopoietic stem cell maintenance
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):573-584
Cuiping Zhang,1 Yvonne N Fondufe-Mittendorf,2 Chi Wang,3 Jin Chen,4
Qiang Cheng,4 Daohong Zhou,5 Yi Zheng,6 Hartmut Geiger6,7 and Ying Liang1
1Departments of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA; 2Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; 3Department of Cancer Biostatistics, University of Kentucky, Lexington, KY, USA; 4Department of Internal Medicine and Computer Science, University of Kentucky, Lexington, KY, USA; 5Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA; 6Cincinnati Children’s Hospital Medical Center, Experimental Hematology and Cancer Biology, Cincinnati, OH, USA and 7Institute for Molecular Medicine, University of Ulm, Ulm, Germany
ABSTRACT
Hematopoietic stem cells provide life-long production of blood cells and undergo self-renewal division in order to sustain the stem cell pool. Homeostatic maintenance of hematopoietic stem cell pool and blood cell production is vital for the organism to survive. We previously reported that latexin is a negative regulator of hematopoietic stem cells in mice. Its natural variation in the expression is inversely correlated with hematopoietic stem cell number. However, the molecular mechanisms reg- ulating latexin transcription remain largely unknown, and the genetic fac- tors contributing to its natural variation are not clearly defined. Here we dis- covered a chromatin protein, high-mobility group protein B2, as a novel transcriptional suppressor of latexin by using DNA pull-down and mass spectrometry. High-mobility 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, sug- gesting that latexin is one of the downstream targets and functional medi- ators of high-mobility 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 expres- sion and lower hematopoietic stem cell number, whereas C allele indicates the lower latexin expression and higher stem cell number. This study reveals for the first time 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 natu- rally occurring genetic variants, in combination with epigenetic regulator, in determining differential gene expression and phenotypic diversity in the hematopoietic stem cell population.
Introduction
Stem cells are key to the homeostatic maintenance of mature and functional cells in a variety of tissues and organs. They have the unique ability to perpetuate them- selves through self-renewal and to replenish dying or damaged cells through multi- lineage differentiation. The balance between self-renewal and differentiation is crit- ical for tissue homeostasis, and any disruption in this balance could lead to serious problems such as tissue degeneration and development of cancer.1 Probably the best-studied adult stem cells are hematopoietic stem cells (HSC), which are respon- sible for life-long production of all hematopoietic lineages.2-4 The total number of HSC is kept constant under steady-state conditions, but it also changes in response
Correspondence:
YING LIANG
ying.liang@uky.edu
Received: September 17, 2018. Accepted: June 5, 2019. Pre-published: June 6, 2019.
doi:10.3324/haematol.2018.207092
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/573
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haematologica | 2020; 105(3)
573
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