Transcriptional regulation of early T‐cell development in the thymus

Abstract

T-cell development occurs in multipotent progenitors arriving in the thymus, which provides a highly specialized microenvironment. Specification and sequential commitment processes to T cells begin in early thymic progenitors upon receiving thymus-specific environmental cues, resulting in the activation of the genetically programmed transcriptional cascade that includes turning on and off numerous transcription factors in a precise manner. Thus, early thymocyte differentiation has been an excellent model system to study cell differentiation processes. This review summarizes recent advances in our knowledge on thymic T-cell development from newly arrived multipotent T-cell progenitors to fully committed T-cell precursors, from the transcriptional regulation perspective. Keywords: T-cell development r Thymus r Transcription factors r Transcriptional regulation r Transcriptional network r T-cell progenitors IntroductionDevelopment requires a complex but precise control of regulatory genes and the regulation of individual gene expression can be achieved by numerous mechanisms such as transcriptional regulation, post-transcriptional modifications, and translational regulation. However, regulation at the transcriptional level is not only the most fundamental since transcription is the first step during gene expression but also the most energy-efficient method since mRNAs are not synthesized at all until required [1]. At the most basic level, transcriptional regulation is achieved at the transcription initiation stage by the interaction of two entities, cis-acting elements of regulatory DNA sequences, such as promoters, enhancers, and silencers, and trans-acting factors of proteins such as transcription factors. A specific interaction between cognate cis-and trans-factors is followed by the recruitment of more general machineries such as transcriptional activators and repressors [2]. Although the basic mechanism of transcriptional regulation by cis-elements and transcription factors is similar, the genomic structure of eukaryotes is far more complex than that of Correspondence: Dr. Wooseok Seo e-mail: wooseok.seo@riken.jp prokaryotes. For example, eukaryotic cis-regulatory DNA elements are not only found in the vicinity of the target gene but can also be present far away from the transcriptional start site, an example is a cluster of cis-elements for Shh (The sonic hedgehog) pathway, which is located 1000 kb away [3]. Therefore, in some cases, regulation of gene expression in eukaryotes inevitably requires long-range interactions between specific DNA sequences, which allow them to be positioned in close proximity to each other. Even though such tertiary structures can be achieved by a variety of mechanisms, including self-association of CCCTC-binding factor (CTCF) proteins bound on insulator sequences or interaction between mediator complexes bound on cis-elements [4], the underlying common scheme is the establishment of chromatin looping.Interactions between transcription factors and cis-elements, as well as chromatin...

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