Developmental regulation of myeloerythroid progenitor function by the Lin28b–let-7–Hmga2 axis

Rowe, R. Grant; Wang, Leo D.; Coma, Sílvia; Han, A-Reum; Mathieu, Ronald; Pearson, Daniel S.; Ross, Samantha; Sousa, Patricia; Nguyen, Phi T.; Rodriguez, Antony; Wagers, Amy J.; Daley, George Q.

doi:10.1084/jem.20151912

Cited by 64 publications

(92 citation statements)

References 66 publications

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“…3 C), the expression of the RNA-binding protein Lin28b was highly enriched, and MIRLET7B was highly depleted. Lin28b can block the bioprocessing of let-7 family microRNAs (miRNAs; Jiang and Baltimore, 2016; Rowe et al, 2016), providing an explanation of why the MIRLET7B host gene (MIRLET7HG) transcript is highly enriched within postnatal γδ thymocytes and AB-derived γδ T cells (Fig. 1 B and Fig.…”

Section: Resultsmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

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In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant γδ T cells occur in humans is not known. Here we found that, unlike postnatal γδ thymocytes, human fetal γδ thymocytes were functionally programmed (e.g., IFNγ, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.

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Section: Resultsmentioning

confidence: 99%

The human fetal thymus generates invariant effector γδ T cells

Tieppo

Papadopoulou

Gatti

et al. 2019

Journal of Experimental Medicine

137

View full text Add to dashboard Cite

show abstract

“…37 HMGA2 is an effector that is involved in the genetic switch wherein let-7 activation in the fetal state causes a shift toward an adult-like myeloid-dominant output. 38 MiR-98, which belongs to the let-7 family, is overexpressed in fetal sclera compared to adult sclera. 39 Considering that miR-4500 shares a seed sequence with let-7/miR-98, we speculated that miR-4500 may have functional role in human development.…”

Section: Discussionmentioning

confidence: 99%

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

Yun

Deng

et al. 2016

Cancer Biology & Therapy

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This study aimed to understand the exact function and potential mechanism of miR-4500 in colorectal cancer (CRC). In this study, the expression of miR-4500 was decreased in both CRC cells and tissues, and downregulated miR-4500 indicated advanced tumor stage and poor survival. By bisulfite sequencing analysis, we found that the CpG island in the promoter region of miR-4500 was hypermethylated in CRC cells and tissues compared with normal control cells and non-tumor tissues, respectively. Functionally, gain-and loss-of-function analyses indicated the tumor suppressor role of miR-4500: it suppressed cell proliferation, cell cycle progression, migration, and invasion. Predictive algorithms and experimental analyses identified HMGA2 as a direct target of miR-4500. Reintroducing HMGA2 impaired the inhibitory effects of miR-4500 on cell growth and motility. Clinically, higher HMGA2 protein expression in CRC tissues was associated with advanced tumor stage and poor survival. An inverse correlation was found between miR-4500 levels and HMGA2 protein expression. Taken together, this study provides the first evidence that miR-4500 functions as a novel tumor suppressor in the miR-4500/HMGA2 axis in colorectal carcinogenesis, and restoring miR-4500 expression might represent a promising therapeutic strategy for CRC.Abbreviations: CRC, Colorectal cancer; HMGA2, high mobility group AT-hook 2; 5-aza, 5-aza-2 0 -deoxycytidine

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“…7 Moreover, Hmga2 was identified as a direct target of Runx1 that led to myeloid cell expansion in the context of Runx1 deficiency. 8 Together, these studies point to a direct functional role of Hmga2 in regulation of stem and progenitor cells in mice and provide an inviting prospect to further elucidate its role in human hematopoiesis. Yet, to date, no functional studies describing the role of HMGA2 in human HSPCs have been described.…”

Section: Introductionmentioning

confidence: 88%

HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells

et al. 2019

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Identification of determinants of fate choices in hematopoietic stem cells (HSCs) is essential to improve the clinical use of HSCs and to enhance our understanding of the biology of normal and malignant hematopoiesis. Here, we show that high-mobility group AT hook 2 (HMGA2), a nonhistone chromosomal-binding protein, is highly and preferentially expressed in HSCs and in the most immature progenitor cell subset of fetal, neonatal, and adult human hematopoiesis. Knockdown of HMGA2 by short hairpin RNA impaired the long-term hematopoietic reconstitution of cord blood (CB)–derived CB CD34+ cells. Conversely, overexpression of HMGA2 in CB CD34+ cells led to overall enhanced reconstitution in serial transplantation assays accompanied by a skewing toward the myeloerythroid lineages. RNA-sequencing analysis showed that enforced HMGA2 expression in CD34+ cells induced gene-expression signatures associated with differentiation toward megakaryocyte-erythroid and myeloid lineages, as well as signatures associated with growth and survival, which at the protein level were coupled with strong activation of AKT. Taken together, our findings demonstrate a key role of HMGA2 in regulation of both proliferation and differentiation of human HSPCs.

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Developmental regulation of myeloerythroid progenitor function by the Lin28b–let-7–Hmga2 axis

Abstract: Daley and collaborators show that endogenous Lin28b drives erythroid-dominant fetal hematopoiesis and that decreases in Lin28b activate adult granulocyte-predominant hematopoiesis.

Cited by 64 publications

References 66 publications

The human fetal thymus generates invariant effector γδ T cells

The human fetal thymus generates invariant effector γδ T cells

MiR-4500 is epigenetically downregulated in colorectal cancer and functions as a novel tumor suppressor by regulating HMGA2

HMGA2 promotes long-term engraftment and myeloerythroid differentiation of human hematopoietic stem and progenitor cells

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