An unsung runt 6e isoform for HSC expansion

Osato, Motomi

doi:10.1182/blood-2014-05-572891

Cited by 2 publications

(2 citation statements)

References 9 publications

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“…These observations support an evolutionarily conserved role for short RUNX1 isoforms in healthy hematopoiesis. 26,27,29 Additionally, we implicated splicing RBPs, not APA machinery, in the regulation of alternative terminal exon polyadenylation. KHDRBS1 has recently been reported to regulate this unique APA category.…”

Section: Discussionmentioning

confidence: 92%

“…Despite this restricted expression, short isoforms of RUNX1 are conserved across species, [26][27][28] playing an important role in healthy HSC pool maintenance. 29 Because RUNX1a mediates HSC expansion, overexpression can be leukemogenic. 20 Indeed, RUNX1a is overexpressed in some patients with acute myeloid leukemia (AML), 14,20 acute lymphoblastic leukemia, 20 or MDS.…”

Section: Introductionmentioning

confidence: 99%

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A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation

Davis¹,

Einstein

Zheng

et al. 2021

Blood Advances

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The proper balance of hematopoietic stem cell (HSC) self-renewal and differentiation is critical for normal hematopoiesis and is disrupted in hematologic malignancy. Among regulators of HSC fate, transcription factors have a well-defined central role, and mutations promote malignant transformation. More recently, studies have illuminated the importance of posttranscriptional regulation by RNA-binding proteins (RBPs) in hematopoiesis and leukemia development. However, the RBPs involved and the breadth of regulation are only beginning to be elucidated. Furthermore, the intersection between posttranscriptional regulation and hematopoietic transcription factor function is poorly understood. Here, we studied the posttranscriptional regulation of RUNX1, a key hematopoietic transcription factor. Alternative polyadenylation (APA) of RUNX1 produces functionally antagonistic protein isoforms (RUNX1a vs RUNX1b/c) that mediate HSC self-renewal vs differentiation, an RNA-processing event that is dysregulated in malignancy. Consequently, RBPs that regulate this event directly contribute to healthy and aberrant hematopoiesis. We modeled RUNX1 APA using a split GFP minigene reporter and confirmed the sensitivity of our model to detect changes in RNA processing. We used this reporter in a clustered regularly interspaced short palindromic repeats (CRISPR) screen consisting of single guide RNAs exclusively targeting RBPs and uncovered HNRNPA1 and KHDRBS1 as antagonistic regulators of RUNX1a isoform generation. Overall, our study provides mechanistic insight into the posttranscriptional regulation of a key hematopoietic transcription factor and identifies RBPs that may have widespread and important functions in hematopoiesis.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation

Davis¹,

Einstein

Zheng

et al. 2021

Blood Advances

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Runx Family Genes in Tissue Stem Cell Dynamics

Wang

Mok

Yokomizo

et al. 2017

Advances in Experimental Medicine and Biology

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The Runx family genes play important roles in development and cancer, largely via their regulation of tissue stem cell behavior. Their involvement in two organs, blood and skin, is well documented. This review summarizes currently known Runx functions in the stem cells of these tissues. The fundamental core mechanism(s) mediated by Runx proteins has been sought; however, it appears that there does not exist one single common machinery that governs both tissue stem cells. Instead, Runx family genes employ multiple spatiotemporal mechanisms in regulating individual tissue stem cell populations. Such specific Runx requirements have been unveiled by a series of cell type-, developmental stage- or age-specific gene targeting studies in mice. Observations from these experiments revealed that the regulation of stem cells by Runx family genes turned out to be far more complex than previously thought. For instance, although it has been reported that Runx1 is required for the endothelial-to-hematopoietic cell transition (EHT) but not thereafter, recent studies clearly demonstrated that Runx1 is also needed during the period subsequent to EHT, namely at perinatal stage. In addition, Runx1 ablation in the embryonic skin mesenchyme eventually leads to complete loss of hair follicle stem cells (HFSCs) in the adult epithelium, suggesting that Runx1 facilitates the specification of skin epithelial stem cells in a cell extrinsic manner. Further in-depth investigation into how Runx family genes are involved in stem cell regulation is warranted.

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An unsung runt 6e isoform for HSC expansion

Cited by 2 publications

References 9 publications

A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation

A CRISPR RNA-binding protein screen reveals regulators of RUNX1 isoform generation

Runx Family Genes in Tissue Stem Cell Dynamics

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