The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

Abstract

SummaryPrior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS) strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC) frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx). Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.

Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis

“…It is also known to regulate hair follicle, intestinal, and hematopoietic stem cell biology (Takeda et al, 2013; Takeda et al, 2011; Zhang et al, 2013). A recent study has implicated HOPX in adult hematopoietic stem cell function though a potential role in regulating embryonic hematopoietic development during mesodermal patterning has not been studied (Zhou et al, 2015). …”

“…We applied this approach to identify molecules that regulate mesodermal fates with a specific focus on HOPX. HOPX is a non-DNA binding homeodomain protein that has been shown to modulate cell fate choices in a wide range of contexts (Jain et al, 2015a; Takeda et al, 2013; Takeda et al, 2011; Trivedi et al, 2010; Zhou et al, 2015). In the current study we provide evidence for a mechanism by which HOPX regulates hemato-endothelial development.…”

“…A recent study has identified a role for HOPX in adult hematopoietic stem cell homeostasis and engraftment (Zhou et al 2015), but did not address embryonic HSC formation. Although we did not observe a significant effect on EMP hematopoiesis in the absence of HOPX, further studies will be required to determine whether HOPX also interacts with the Wnt pathway to regulate definitive, multilineage hematopoiesis and particularly embryonic HSC formation, as specification of multilineage hematopoiesis in human PSC models remains inefficient and thus challenging to assess with current differentiation protocols.…”

Epigenetic biomarkers of promoter DNA methylation in the new era of cancer treatment

“…Nevertheless, frequent cancer‐specific methylation is rare across the whole genome, and few methylated genes have been validated as sites of its frequent aberration with high specificity in human cancer. Rigorous screening by PUM has repeatedly unveiled novel cancer‐prone methylation genes associated with tumor suppressive functions, such as the encoding homeobox only protein homeobox ( HOPX ) gene has been identified in various cancers, and HOPX expression has been independently revealed to be a biomarker representing differentiation or quiescent stem cell signatures in normal organ tissues . Hence, epigenetic changes in differentiation markers may be essential for the initiation of cancer cell growth.…”

The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities

“…Since each strain is renewable, diverse molecular, proteomic, metabolomic, and clinical phenotypic data can be collected ad infinitum in multiple mice of the same strain/genotype, thus facilitating systems genetics analyses. Studies with the HMDP have been applied to a variety of traits relevant to human CAD and consistently identified positional candidate genes for follow-up functional experiments [55–61]. …”