One of the important questions in immunology is how immune effector cells acquire the ability to express a set of genes whose products confer them with the specialized immune functions. Our lab studies the signaling and transcriptional regulation of the expression of genes important in the normal and diseased immune system. We investigate how master transcription factors regulate the set of genes during differentiation of progenitors/precursors into immune effector cells and how immune genes in the differentiated effector cells detect signal inputs triggered by extracellular immunological stimuli and convert them into transcriptional outputs.

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As illustrated in Figure 1, master transcription factors GATA2 and MITF act as pioneering factors to “Open Up” chromatin of their targeted transcription factor genes, such as mast cell-specific transcription factors MITF, MCTF1 and MCTF2, then act together with MITF, MCTF1 and MCTF2 along with common transcription factors, such as SP1 and AP1, to regulate their target genes whose products carry out immune functions in a feed-forward manner.

Pioneer factors induce a network of transcription factors that control the expression of genes that confer effector cells with specified functions.

Figure 1. Pioneer factors induce a network of transcription factors that control the expression of genes that confer effector cells with specified functions.

 

Figure 2 shows how immune effector cells detect external stimuli in the normal and diseased conditions and convert them into transcriptional outputs. Transcription factors become activated after external stimulation. These transcription factors bind to promoters and enhancers to form a transcription complex via a looping mechanism. We combine genomic approaches, including histone ChIP-seq, ATAC-seq, transcription factor ChIP-seq and RNA-seq, and with experimental approaches to study how individual enhancers and their associated transcription factors regulate immune gene expression. We determine the function of enhancers and their associated transcription factors in primary cells, cell line and mice using the CRISPR-mediated transcription factor binding site editing or transcription repression. We study effector cells including helper T cells, innate lymphoid cells, basophils and mast cells to determine how they function in the diseased immune conditions, such as food allergy and asthma, parasitic infection and autoimmune disease. Because some individuals are more susceptible to develop certain diseases and develop more severe forms of the diseases, we are also interested in studying how regulatory variants found in the promoters and enhancers contribute to disease susceptibility and severity.

Transcription factors detect signals generated by external stimulation and convert them into transcriptional outputs by bridging promoters and enhancers.

Figure 2. Transcription factors detect signals generated by external stimulation and convert them into transcriptional outputs by bridging promoters and enhancers.