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Unraveling the mechanism of GATA1s-m...

Byrska-Bishop, Marta.

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Unraveling the mechanism of GATA1s-mediated blood disorders using functional genomics in pluripotent stem cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Unraveling the mechanism of GATA1s-mediated blood disorders using functional genomics in pluripotent stem cells./
作者:	Byrska-Bishop, Marta.
面頁冊數:	199 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-03(E), Section: B.
Contained By:	Dissertation Abstracts International77-03B(E).
標題:	Bioinformatics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3730604
ISBN:	9781339168913

Unraveling the mechanism of GATA1s-mediated blood disorders using functional genomics in pluripotent stem cells.
Byrska-Bishop, Marta.

Unraveling the mechanism of GATA1s-mediated blood disorders using functional genomics in pluripotent stem cells. - 199 p.

Source: Dissertation Abstracts International, Volume: 77-03(E), Section: B.

Thesis (Ph.D.)--The Pennsylvania State University, 2015.

GATA1 is a hematopoietic transcription factor important for the development of erythroid, megakaryocytic, and several myeloid lineages. Normally, a human hematopoietic cell expresses both a full-length form of GATA1 (GATA1fl) and a short form (GATA1s) that lacks the N-terminal transactivation domain (NAD). Germline GATA1 mutations that result in exclusive production of GATA1s (referred to as "GATA1s mutations") have been identified in patients with congenital hypoplastic anemia and neutropenia, as well as Diamond-Blackfan anemia. In individuals with Down syndrome (DS), somatic GATA1s mutations lead to transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia.

ISBN: 9781339168913Subjects--Topical Terms:

553671
Bioinformatics.

Unraveling the mechanism of GATA1s-mediated blood disorders using functional genomics in pluripotent stem cells.
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245 1 0 $a Unraveling the mechanism of GATA1s-mediated blood disorders using functional genomics in pluripotent stem cells.
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500 $a Source: Dissertation Abstracts International, Volume: 77-03(E), Section: B.
500 $a Adviser: Ross C. Hardison.
502 $a Thesis (Ph.D.)--The Pennsylvania State University, 2015.
520 $a GATA1 is a hematopoietic transcription factor important for the development of erythroid, megakaryocytic, and several myeloid lineages. Normally, a human hematopoietic cell expresses both a full-length form of GATA1 (GATA1fl) and a short form (GATA1s) that lacks the N-terminal transactivation domain (NAD). Germline GATA1 mutations that result in exclusive production of GATA1s (referred to as "GATA1s mutations") have been identified in patients with congenital hypoplastic anemia and neutropenia, as well as Diamond-Blackfan anemia. In individuals with Down syndrome (DS), somatic GATA1s mutations lead to transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia.
520 $a I investigated the function of human GATA1s by analyzing genomic data from induced pluripotent stem cells (iPSCs) obtained from somatic tissues of patients with DS-associated TMD and congenital macrocytic anemia due to a germline GATA1s mutation.
520 $a Microarray transcriptome profiles of iPSC-derived progenitors revealed that GATA1s upregulated mostly megakaryocytic and myeloid genes, and downregulated predominantly erythroid genes. Furthermore, compared to controls, erythropoiesis by GATA1s iPSCs was markedly reduced, while megakaryopoiesis and myelopoiesis were enhanced.
520 $a Single cell expression profiling of selected hematopoietic genes revealed heterogeneity of cell fate preferences within progenitor cell populations. Additionally, single cell expression analysis demonstrated that small changes in expression of many genes contributed to the GATA1s-mediated change in lineage bias from erythroid to myelo-megakaryocytic lineage fate.
520 $a To provide a mechanistic explanation of the observed phenotype, I integrated genome-wide differential binding profiles of GATA1 isoforms obtained using ChIPseq with differential transcriptome response to the presence or absence of GATA1fl or GATA1s in murine megakaryocyte-erythroid bipotential progenitor cells, G1MEs.
520 $a I demonstrated that loss of the NAD impairs erythropoiesis and biases cells towards myelo-megakaryopoiesis due to: (i) a failure to efficiently bind to a subset of GATA1 erythroid target sites resulting in the lack of induction of erythroid genes, and (ii) a failure to repress a subset of myelo-megakaryocytic genes upon successful binding to DNA. I identified SMAD1 and LMO2 as candidate co-factors that might be involved in NAD-dependent selective chromatin occupancy of GATA1 at erythroid targets and repression of myelo-megakaryocytic genes, respectively.
520 $a I propose a new model for GATA1 function in hematopoiesis, according to which an imbalance in the relative expression levels of GATA1 isoforms within an individual cell might lead to a bias in cell fate. Specifically, based on the results of our study, I hypothesize that cells expressing predominantly GATA1fl are more likely to differentiate towards erythroid lineage, while cells expressing predominantly GATA1s are more likely to differentiate towards myeloid and megakaryocytic lineages.
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