Meifang Dai

University of Science and Technology of China

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Yuan Zhuang

Chinese PLA General Hospital

Baojun Zhang

Tangshan College

Yen‐Yu Lin

Taipei Veterans General Hospital

Robert J. Barndt

University of Pittsburgh Medical Center

Li‐Hua Pan

Hefei University of Technology

Chunlei Cang

University of Science and Technology of China

Wenping Zeng

Hefei National Center for Physical Sciences at Nanoscale

Jianxuan Wu

Duke Medical Center

Qi-Jing Li

Agency for Science, Technology and Research

Lili Qu

University of Science and Technology of China

Cooperative Institutions

University of Science and Technology of China

Duke University Hospital

Duke Medical Center

Duke University

Hefei National Center for Physical Sciences at Nanoscale

Chinese Academy of Sciences

CAS Key Laboratory of Urban Pollutant Conversion

Huazhong Agricultural University

Sichuan University

Huazhong University of Science and Technology

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A Novel Role for HEB Downstream or Parallel to the Pre-TCR Signaling Pathway During αβ Thymopoiesis

The Journal of Immunology (1999)

Robert J. Barndt Meifang Dai Yuan Zhuang

Abstract TCR gene rearrangement and expression are central to the development of clonal T lymphocytes. The pre-TCR complex provides the first signal instructing differentiation and proliferation events during the transition from CD4−CD8−TCR− double negative (DN) stage to CD4+CD8+ double positive (DP) stage. How the pre-TCR signal leads to downstream gene expression is not known. HeLa E-box binding protein (HEB), a basic helix-loop-helix transcription factor, is abundantly detected in thymocytes and is thought to regulate E-box sites present in many T cell-specific gene enhancers, including TCR-α, TCR-β, and CD4. Targeted disruption of HEB results in a 5- to 10-fold reduction in thymic cellularity that can be accounted for by a developmental block at the DN to DP stage transition. Specifically, a dramatic increase in the CD4low/−CD8+CD5lowHSA+TCRlow/− immature single positive population and a concomitant decrease in the subsequent DP population are observed. Adoptive transfer test shows that this defect is cell-autonomous and restricted to the αβ T cell lineage. Introduction of an αβ TCR transgene into the HEBko/ko background is not sufficient to rescue the developmental delay. In vivo CD3 cross-linking analysis of thymocytes indicates that TCR signaling pathway in the HEBko/ko mice appears intact. These findings suggest an essential function of HEB in early T cell development, downstream or parallel to the pre-TCR signaling pathway.

Double negative

10.4049/jimmunol.163.6.3331

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A mosaic analysis system with Cre or Tomato expression in the mouse

Proceedings of the National Academy of Sciences (2020)

Qun Wang Yen‐Yu Lin Baojun Zhang Jianxuan Wu Sumedha Roy

Significance Somatic mutations are the driving force of many age-related diseases such as cancer and hematopoietic failure. A challenge in the field is to evaluate health impact of somatic mutations prior to the appearance of disease symptoms. We describe a genetic tool named MASCOT (mosaic analysis system with Cre or Tomato) for mosaic analysis of somatic mutations that drive clonal hematopoiesis and lymphomagenesis. MASCOT can be applied to mosaic analysis of broad tissue types, and thus provides a valuable tool to aid functional dissection of somatic mutations in studies of development and disease.

10.1073/pnas.2014308117

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Metabolomic profiling of single enlarged lysosomes

Nature Methods (2021)

Hongying Zhu Qianqian Li Tiepeng Liao Xiang Yin Qi Chen

Metabolome

10.1038/s41592-021-01182-8

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E2A Promotes the Survival of Precursor and Mature B Lymphocytes

The Journal of Immunology (2006)

Adam S. Lazorchak Jason Wojciechowski Meifang Dai Yuan Zhuang

Abstract The basic helix-loop-helix transcription factor E2A is an essential regulator of B lymphocyte lineage commitment and is required to activate the expression of numerous B lineage-specific genes. Studies involving ectopic expression of Id proteins, which inhibit E2A as well as other basic helix-loop-helix proteins such as HEB, suggest additional roles of E2A at later stages of B cell development. We use E2A-deficient and E2A and HEB double-deficient pre-B cell lines to directly assess the function of E2A and HEB in B cell development after lineage commitment. We show that, in contrast to the established role of E2A in lineage commitment, elimination of E2A and HEB in pre-B cell lines has only a modest negative impact on B lineage gene expression. However, E2A single and E2A and HEB double-deficient but not HEB single-deficient cell lines show dramatically enhanced apoptosis upon growth arrest. To address the possible role of E2A in the regulation of B cell survival in vivo, we crossed IFN-inducible Cre-transgenic mice to E2A conditional mice. Cre-mediated E2A deletion resulted in a block in bone marrow B cell development and a significant reduction in the proportion and total number of splenic B cells in these mice. We show that Cre-mediated deletion of E2A in adoptively transferred mature B cells results in the rapid depletion of the transferred population within 24 h of Cre induction. These results reveal that E2A is not required to maintain B cell fate but is essential in promoting pre-B and B cell survival.

Basic helix-loop-helix

Ectopic expression

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10.4049/jimmunol.177.4.2495

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Citations (41)

Regulation of E2A gene expression in B-lymphocyte development

Molecular Immunology (2004)

Yuan Zhuang Annette M. Jackson Li‐Hua Pan Kang Shen Meifang Dai

Lineage (genetic)

10.1016/j.molimm.2003.11.031

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Citations (52)

Functions of E2A-HEB Heterodimers in T-Cell Development Revealed by a Dominant Negative Mutation of HEB

Molecular and Cellular Biology (2000)

Robert J. Barndt Meifang Dai Yuan Zhuang

Lymphocyte development and differentiation are regulated by the basic helix-loop-helix (bHLH) transcription factors encoded by the E2A and HEB genes. These bHLH proteins bind to E-box enhancers in the form of homodimers or heterodimers and, consequently, activate transcription of the target genes. E2A homodimers are the predominant bHLH proteins present in B-lineage cells and are shown genetically to play critical roles in B-cell development. E2A-HEB heterodimers, the major bHLH dimers found in thymocyte extracts, are thought to play a similar role in T-cell development. However, disruption of either the E2A or HEB gene led to only partial blocks in T-cell development. The exact role of E2A-HEB heterodimers and possibly the E2A and HEB homodimers in T-cell development cannot be distinguished in simple disruption analysis due to a functional compensation from the residual bHLH homodimers. To further define the function of E2A-HEB heterodimers, we generated and analyzed a dominant negative allele of HEB, which produces a physiological amount of HEB proteins capable of forming nonfunctional heterodimers with E2A proteins. Mice carrying this mutation show a stronger and earlier block in T-cell development than HEB complete knockout mice. The developmental block is specific to the alpha/beta T-cell lineage at a stage before the completion of V(D)J recombination at the TCRbeta gene locus. This defect is intrinsic to the T-cell lineage and cannot be rescued by expression of a functional T-cell receptor transgene. These results indicate that E2A-HEB heterodimers play obligatory roles both before and after TCRbeta gene rearrangement during the alpha/beta lineage T-cell development.

10.1128/mcb.20.18.6677-6685.2000

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Citations (181)

P-031 Isochromosome 17q10 in MDS/MPN are frequently associated with TET2 mutations and transformation termination of acute megakaryoblastic leukemia

Leukemia Research (2013)

Hongjing Zhou L B Liao L.L. Zhou H. Li Ran Cao

Acute megakaryoblastic leukemia

Isochromosome

10.1016/s0145-2126(13)70080-8

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A T Cell Intrinsic Role of Id3 in a Mouse Model for Primary Sjögren's Syndrome

Immunity (2004)

Hongmei Li Meifang Dai Yuan Zhuang

Thymectomy

Adoptive Cell Transfer

10.1016/j.immuni.2004.08.013

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Citations (130)

Id3 and Id2 collaboratively regulate innate-like γδ T cell development (HEM3P.275)

The Journal of Immunology (2014)

Baojun Zhang Yen‐Yu Lin Meifang Dai Yuan Zhuang

Abstract γδ T cells expressing the Vγ1.1 and Vδ6.3 TCR chains are one of growing numbers of recently characterized innate-like lymphocytes. Id3 has been shown to be a major transcription regulator to prevent the development and expansion of this population. We showed that deletion of Id3 resulted in a dramatic expansion of Vγ1.1Vδ6.3 T cells on the C57BL/6 background. This phenotype is in contrast to the much milder phenotype when the Id3 mutation was initially characterized on the 129/sv background. We conducted a quantitative trait analysis in search of the presumed Id3 modifier(s). Id2 was mapped as a major modifier of Id3 in suppressing Vγ1.1Vδ6.3 cell expansion. This mapping result was further confirmed by introduction of the targeted allele of Id2 to the Id3 mutant background. Our study led to four major observations: first, a decrease in Id2 expression on Id3 deficiency background promotes expansion of Vγ1.1Vδ6.3 cells. Second, complete elimination of both Id2 and Id3 genes triggers apoptosis instead of further expansion of Vγ1.1Vδ6.3 cells. Third, Id3 and Id2 collaboratively control survival and expansion of the γδ lineage through regulating a proper threshold of E proteins. Finally, Id proteins seem to control cell survival and expansion post Vγ1.1Vδ6.3 lineage specification. Based on these findings, we propose a dual safety mechanism to explain the role of Id3 and Id2 in regulating the population size of Vγ1.1Vδ6.3 T cells.

Lineage (genetic)

10.4049/jimmunol.192.supp.51.4

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Lysosomal cation channel TRPML1 suppression sensitizes acute myeloid leukemia cells to chemotherapeutics by inhibiting autophagy

Molecular and Cellular Biochemistry (2024)

Meifang Dai Bingqian Lin Hao Li Youming Wang Miaomiao Wu

10.1007/s11010-024-05054-5

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Citations (1)