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Start Over Author "Emery, H." Journal blood advances
17 results on '"Emery, H."'

10. Blood disease–causing and –suppressing transcriptional enhancers: general principles and GATA2 mechanisms

Author

Emery H. Bresnick and Kirby D. Johnson

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Intensive scrutiny of human genomes has unveiled considerable genetic variation in coding and noncoding regions. In cancers, including those of the hematopoietic system, genomic instability amplifies the complexity and functional consequences of variation. Although elucidating how variation impacts the protein-coding sequence is highly tractable, deciphering the functional consequences of variation in noncoding regions (genome reading), including potential transcriptional-regulatory sequences, remains challenging. A crux of this problem is the sheer abundance of gene-regulatory sequence motifs (cis elements) mediating protein-DNA interactions that are intermixed in the genome with thousands of look-alike sequences lacking the capacity to mediate functional interactions with proteins in vivo. Furthermore, transcriptional enhancers harbor clustered cis elements, and how altering a single cis element within a cluster impacts enhancer function is unpredictable. Strategies to discover functional enhancers have been innovated, and human genetics can provide vital clues to achieve this goal. Germline or acquired mutations in functionally critical (essential) enhancers, for example at the GATA2 locus encoding a master regulator of hematopoiesis, have been linked to human pathologies. Given the human interindividual genetic variation and complex genetic landscapes of hematologic malignancies, enhancer corruption, creation, and expropriation by new genes may not be exceedingly rare mechanisms underlying disease predisposition and etiology. Paradigms arising from dissecting essential enhancer mechanisms can guide genome-reading strategies to advance fundamental knowledge and precision medicine applications. In this review, we provide our perspective of general principles governing the function of blood disease–linked enhancers and GATA2-centric mechanisms.

Published
2019
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11. RNA-Regulatory Exosome Complex Suppresses an Apoptotic Program to Confer Erythroid Progenitor Cell Survival In Vivo

Author

Isabela Fraga de Andrade, Kirby D. Johnson, Charu Mehta, Colin N. Dewey, Uttiya Basu, and Emery H. Bresnick

Subjects
Hematology
Abstract

The RNA-regulatory exosome complex (EC) posttranscriptionally and cotranscriptionally processes and degrades RNAs in a context-dependent manner. Although the EC functions in diverse cell types, its contributions to stem and progenitor cell development are not well understood. Previously, we demonstrated that the transcriptional regulator of erythrocyte development, GATA1, represses EC subunit genes, and the EC maintains erythroid progenitors in vitro. To determine if this mechanism operates in vivo, we used the hematopoietic-specific Vav1-Cre and “conditional by inversion” mouse system to ablate Exosc3, encoding an EC structural subunit. Although Exosc3C/C Cre+ embryos developed normally until embryonic day 14.5, Exosc3 ablation was embryonic lethal and severely reduced erythromyeloid progenitor activity. RNA sequencing analysis of Exosc3-ablated burst-forming unit-erythroid revealed elevated transcripts encoding multiple proapoptotic factors, and the mutant erythroid progenitors exhibited increased apoptosis. We propose that the EC controls an ensemble of apoptosis-regulatory RNAs, thereby promoting erythroid progenitor survival and developmental erythropoiesis in vivo.

Published
2022

14. GATA2 deficiency elevates interferon regulatory factor-8 to subvert a progenitor cell differentiation program

Author

Kirby D. Johnson, Alexandra A. Soukup, and Emery H. Bresnick

Subjects
GATA2 Transcription Factor, GATA2 Deficiency, Interferon Regulatory Factors, Humans, Cell Differentiation, Hematology, Hematopoiesis
Abstract

Cell type-specific transcription factors control stem and progenitor cell transitions by establishing networks containing hundreds of genes and proteins. Network complexity renders it challenging to discover essential versus modulatory or redundant components. This scenario is exemplified by GATA2 regulation of hematopoiesis during embryogenesis. Loss of a far upstream Gata2 enhancer (−77) disrupts the GATA2-dependent transcriptome governing hematopoietic progenitor cell differentiation. The aberrant transcriptome includes the transcription factor interferon regulatory factor 8 (IRF8) and a host of innate immune regulators. Mutant progenitors lose the capacity to balance production of diverse hematopoietic progeny. To elucidate mechanisms, we asked if IRF8 is essential, contributory, or not required. Reducing Irf8, in the context of the −77 mutant allele, reversed granulocytic deficiencies and the excessive accumulation of dendritic cell committed progenitors. Despite many dysregulated components that control vital transcriptional, signaling, and immune processes, the aberrant elevation of a single transcription factor deconstructed the differentiation program.

Published
2021

16. Human GATA2mutations and hematologic disease: how many paths to pathogenesis?

Author

Bresnick, Emery H., Jung, Mabel M., and Katsumura, Koichi R.

Abstract

The surge of human genetic information, enabled by increasingly facile and economically feasible genomic technologies, has accelerated discoveries on the relationship of germline genetic variation to hematologic diseases. For example, germline variation in GATA2, encoding a vital transcriptional regulator of multilineage hematopoiesis, creates a predisposition to bone marrow failure and acute myeloid leukemia termed GATA2 deficiency syndrome. More than 300 GATA2variants representing missense, truncating, and noncoding enhancer mutations have been documented. Although these variants can diminish GATA2 expression and/or function, the functional ramifications of many variants are unknown. Studies using genetic rescue and knockin mouse systems have established that GATA2mutations differentially affect molecular processes in distinct target genes and within a single target cell. Considering that target genes for a transcription factor can differ in sensitivity to altered levels of the factor, and transcriptional mechanisms are often cell type specific, the context-dependent consequences of GATA2mutations in experimental systems portend the complex phenotypes and interindividual variation of GATA2 deficiency syndrome. This review documents GATA2human genetics and the state of efforts to traverse from physiological insights to pathogenic mechanisms.

Published
2020
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17. Gata2+9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T cell development

Author

You, Xiaona, Zhou, Yun, Chang, Yuan-I, Kong, Guangyao, Ranheim, Erik A., Johnson, Kirby D., Soukup, Alexandra A., Bresnick, Emery H., and Zhang, Jing

Abstract

Mammalian GATA2gene encodes a dual zinc finger transcription factor, which is essential for hematopoietic stem cell (HSC) generation in the aorta, gonad, mesonephros (AGM) region, HSC self-renewal, and specification of progenitor cell fates. Previously, we demonstrated that Gata2expression in AGM is controlled by its intronic +9.5 enhancer. Gata2+9.5 deficiency removes the E-box motif and the GATA site and depletes fetal liver HSCs. However, whether this enhancer has an essential role in regulating adult hematopoiesis has not been established. Here, we evaluate Gata2+9.5 enhancer function in adult hematopoiesis. +9.5+/-bone marrow cells displayed reduced T cell reconstitution in a competitive transplant assay. Donor-derived analysis demonstrated a previously unrecognized function of the +9.5 enhancer in T cell development at the lymphoid-primed multipotent progenitor stage. Moreover, +9.5+/-adult HSCs displayed increased apoptosis and reduced long-term self-renewal capability in comparison with wild-type (WT) HSCs. These phenotypes were more moderate than those of Gata2+/-HSCs. Consistent with the phenotypic characterization, Gata2expression in +9.5+/-LSKs was moderately higher than that in Gata2+/-LSKs, but lower than that in WT LSKs. Our data suggest that +9.5deficiency compromises, without completely abrogating, Gata2expression in adult HSCs.

Published
2021
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