Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration

Yan, Xiao; Himburg, Heather A.; Pohl, Katherine; Quarmyne, Mamle; Tran, Elizabeth; Zhang, Yurun; Fang, Tiancheng; Kan, Jenny; Chao, Nelson J.; Zhao, Liman; Doan, Phuong L.; Chute, John P.

doi:10.1016/j.celrep.2016.10.025

Cited by 24 publications

(23 citation statements)

References 45 publications

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“…66,67 Studies of Grb10 deficient mice demonstrated Grb10 ’s role in hematopoietic regeneration in vivo . 68 Additionally, in a transcriptome study of CD4+ Effector Memory T cells (CD4 + T EM ), GRB10 was the most significantly downregulated gene after T-cell receptor stimulation. 69 Notably, in both human and mouse, GRB10 mRNA is highly alternatively spliced, resulting in four to seven unique isoforms.…”

Section: Resultsmentioning

confidence: 99%

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

McArthur

Rinker

Capra

2020

Preprint

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11 12 Background: Nearly all Eurasians have ~2% Neanderthal ancestry due to several events of 13 inbreeding between anatomically modern humans and archaic hominins. Previous studies 14 characterizing the legacy of Neanderthal ancestry in modern Eurasians have identified 15 examples of both adaptive and deleterious effects of admixture. However, we lack a 16 comprehensive understanding of the genome-wide influence of Neanderthal introgression on 17 modern human diseases and traits. 18 Results: We integrate recent maps of Neanderthal ancestry with well-powered association 19 studies for more than 400 diverse traits to estimate heritability enrichment patterns in regions of 20 the human genome tolerant of Neanderthal ancestry and in introgressed Neanderthal variants 21 themselves. First, we find that variants in regions tolerant of Neanderthal ancestry are depleted 22 131We find three exceptions to this complex trait heritability depletion; sunburn (1.16x, P = 132 0.3), skin color (1.21x, P = 0.4), and tanning (1.25x, P = 0.4) are not depleted among regions 133 that retain Neanderthal ancestry (Fig. 1B). These three traits are genetically correlated with 134 magnitudes between r = 0.55 and 0.86. Several previous hypotheses suggest that the 135 introgression of Neanderthal alleles related to hair and skin pigmentation could have provided 136 non-African AMHs with adaptive benefits as they moved to higher latitudes. 3,4,17,18 The 137 exceptions to the overall depletion we observe for skin traits suggest that regions of the human 138 genome involved in skin pigmentation were more tolerant of Neanderthal introgression than 139 regions of the genome associated with other traits. 140 141

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Section: Resultsmentioning

confidence: 99%

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

McArthur

Rinker

Capra

2020

Preprint

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“…Chemoradiation-based conditioning regimens for HSCT as well as standard induction regimens for hematological malignancies are often associated with cytopenias resulting from the myelosuppressive injury of the endogenous HSPCs. Prior studies have shown that HSPCs undergo mTOR activation during myelosuppressive recovery (Baumgartner et al, 2018) and that mTORC1 inhibition delays hematopoietic recovery (Yan et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Endothelial mTOR maintains hematopoiesis during aging

Ramalingam

Poulos

Gutkin

et al. 2020

Journal of Experimental Medicine

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Aging leads to a decline in hematopoietic stem and progenitor cell (HSPC) function. We recently discovered that aging of bone marrow endothelial cells (BMECs) leads to an altered crosstalk between the BMEC niche and HSPCs, which instructs young HSPCs to behave as aged HSPCs. Here, we demonstrate aging leads to a decrease in mTOR signaling within BMECs that potentially underlies the age-related impairment of their niche activity. Our findings reveal that pharmacological inhibition of mTOR using Rapamycin has deleterious effects on hematopoiesis. To formally determine whether endothelial-specific inhibition of mTOR can influence hematopoietic aging, we conditionally deleted mTOR in ECs (mTOR(ECKO)) of young mice and observed that their HSPCs displayed attributes of an aged hematopoietic system. Transcriptional profiling of HSPCs from mTOR(ECKO) mice revealed that their transcriptome resembled aged HSPCs. Notably, during serial transplantations, exposure of wild-type HSPCs to an mTOR(ECKO) microenvironment was sufficient to recapitulate aging-associated phenotypes, confirming the instructive role of EC-derived signals in governing HSPC aging.

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“…qRT-PCR analysis confirmed Grb10 and Tgfbr3 expression were reduced in −77 −/− R1 cells (Figure 6B). The signaling adapter GRB10 is implicated in promoting HSC self-renewal and regeneration (Yan et al, 2016). Tgfbr3 , which encodes TGFβ receptor type III (Wang et al, 1991), is a marker of late BFU-Es (Gao et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…The latter genes included Ryk, Tgfbr3 and Grb10 , encoding hematopoietic signaling components (Famili et al, 2016; Gao et al, 2016; Povinelli and Nemeth, 2014; Povinelli et al, 2015; Randrianarison-Huetz et al, 2010; Yan et al, 2016), and other factors not implicated in red cell biology. Based on the large reduction in Ryk expression in −77 −/− R1 cells and reduced CFU activity upon Ryk knockdown, Ryk signaling may constitute an important determinant of erythroid precursor cell maturation and/or function.…”

Section: Discussionmentioning

confidence: 99%

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

et al. 2017

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SUMMARY Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies including leukemia. GATA-2-regulated enhancers regulate Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5 kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The −77 kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiation. Since +9.5−/− embryos are HSC-deficient, it was unclear whether the +9.5 functions in progenitors or if GATA-2 expression in progenitors solely requires −77. We further dissected the mechanisms using −77;+9.5 compound heterozygous (CH) mice. The embryonic lethal CH mutation depleted megakaryocyte-erythrocyte progenitors (MEPs). While the +9.5 suffices for HSC generation, the −77 and +9.5 must reside on one allele to induce MEPs. The −77 generated Burst Forming Unit-Erythroid through induction of GATA-1 and other GATA-2 targets. The enhancer circuits controlled signaling pathways that orchestrate a GATA factor-dependent blood development program.

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Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration

Cited by 24 publications

References 45 publications

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

Quantifying the contribution of Neanderthal introgression to the heritability of complex traits

Endothelial mTOR maintains hematopoiesis during aging

Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

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