Cell lineage decisions during development require strict gene regulation by complex networks of multiple transcription factors and collaborating factors. During fate decisions, key transcription factors (TFs) drive precursors into one lineage while inactivating """"""""alternative fate genes"""""""". Silenced states of a subset of """"""""alternativ fate genes"""""""" are heritably maintained through epigenetic silencing. Epigenetic silencing is globally important for normal cell development and commonly altered in many types of cancers. Establishment of epigenetic silencing involves recruitment of enzyme activities mediating repressive histone methylation and DNA methylation. These enzyme activities are thought to be delivered by specific sets of TFs in a locus- specific manner. However, the mechanisms by which these TFs drive cel fate decisions and then establish epigenetic silencing are not completely understood. In this proposal, we will study crosstalk between key TFs driving T cell lineage choices and epigenetic modifiers that ultimately establish cell lineage identities. T lymphocyte development is an excellent system to tackle these questions because of our strong background knowledge on developmental processes and requirements for TFs. Specifically, we will study functions of Runx transcription factors in gene repression in the context of fate decisions and epigenetic silencing of """"""""alternative fate genes"""""""". Our efforts will be focused on study of functional collaborations between Runx proteins and their interacting factors that drive and stabilize the fate choice processes. Because Runx proteins are involved in normal development of many cell types, and their functions are frequently altered in leukemia, knowledge obtained through our study of Runx-mediated genetic and epigenetic regulation during T cell development would provide substantial insights into stable gene regulation mechanisms widely used in many cell types as well as altered genetic programs causing cancers.
Diverse cell types are continuously generated from stem/progenitor cells to maintain functional cell compartments. During cell differentiation, a specific set of genes is turned-on or -off by transcription factors, and these distinct states of gene expression are stably maintained. In this study, I propose to investigate the gene regulatory mechanisms that are critical for maintaining cell type diversity in animals and humans.
|Chou, Chun; Verbaro, Daniel J; Tonc, Elena et al. (2016) The Transcription Factor AP4 Mediates Resolution of Chronic Viral Infection through Amplification of Germinal Center B Cell Responses. Immunity 45:570-82|
|Egawa, Takeshi (2015) Regulation of CD4 and CD8 coreceptor expression and CD4 versus CD8 lineage decisions. Adv Immunol 125:1-40|
|Kim, Byungil; Sasaki, Yo; Egawa, Takeshi (2015) Restriction of Nonpermissive RUNX3 Protein Expression in T Lymphocytes by the Kozak Sequence. J Immunol 195:1517-23|
|Ebihara, Takashi; Song, Christina; Ryu, Stacy H et al. (2015) Runx3 specifies lineage commitment of innate lymphoid cells. Nat Immunol 16:1124-33|
|Collins, Patrick L; Kyle, Katherine E; Egawa, Takeshi et al. (2015) The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc Natl Acad Sci U S A 112:8367-72|
|Chou, Chun; Egawa, Takeshi (2015) Myc or no Myc, that is the question. EMBO J 34:1990-1|
|Egawa, Takeshi (2014) Continued mission of ThPOK. Nat Immunol 15:900-2|
|Chou, Chun; Pinto, Amelia K; Curtis, Jonathan D et al. (2014) c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nat Immunol 15:884-93|
|Boucheron, Nicole; Tschismarov, Roland; GÃ¶schl, Lisa et al. (2014) CD4(+) T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. Nat Immunol 15:439-48|
|Satpathy, Ansuman T; BriseÃ±o, Carlos G; Cai, Xiongwei et al. (2014) Runx1 and CbfÎ² regulate the development of Flt3+ dendritic cell progenitors and restrict myeloproliferative disorder. Blood 123:2968-77|
Showing the most recent 10 out of 13 publications