Genome-Wide Analysis of Transcription Factors Ascl1 and Ptf1a in Development and Cancer




Borromeo, Mark Dominic

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Cell fate specification in the developing embryo relies on combinations of transcription factors to regulate tissue specific gene programs. Many of the same transcription factors can be found in multiple tissue types and are crucial for their development, and at other times these same factors can be misused in disease states. The basic helix-loop-helix (bHLH) factors Ascl1 and Ptf1a are examples of factors that give rise to and function in multiple tissues. Ascl1 and Ptf1a are essential for generating the correct number and sub-type of neurons in multiple regions of the nervous system. In addition, Ptf1a is required in the developing pancreas for both its formation and maturation, while Ascl1 is crucial for tumor growth in malignant small cell lung carcinoma (SCLC). It is unknown if Ascl1 and Ptf1a directly regulate different genes programs in these disparate tissues. Furthermore, Ptf1a and Ascl1 are members of same transcription factor family, which recognize and bind a similar DNA sequence. How these two factors achieve specificity of DNA binding and gene target selection in vivo is unknown. These questions have long been unanswered due in part to the lack of known direct transcriptional targets. Thus, to understand how Ascl1 and Ptf1a function in these processes, the direct transcriptional targets were identified genome-wide in the multiple tissues using ChIP-Seq and RNA-Seq. Overwhelmingly, Ascl1 and Ptf1a directly regulate different gene programs important for each tissue. Within a given tissue, the specificity of Ascl1 and Ptf1a function is partly explained by their differences in E-box sequence preferences. Ptf1a and Ascl1 are co-expressed in a subset of cells in the dorsal neural tube, and comparative analysis of their binding sites show that they bind a common E-box. However, Ptf1a can also bind a distinct E-box, which is found enriched in binding sites unique to Ptf1a. However, analysis of Ascl1 binding in SCLC and Ptf1a binding in the developing pancreas, shows that their E-box preferences change and does not reflect the same type of E-box they bind in the neural tube. Mechanisms in addition to E-box specificity are likely in use because tissue specific binding coincides with tissue-specific chromatin accessibility and enrichment of lineage-specific transcription factor binding motifs. Thus, Ascl1 and Ptf1a make use of different tissue-specific co-factors to regulate tissue-specific genes. This study provides insights into how a single factor can regulate the transcription of different genes in different tissue types, and how two related E-box binding proteins regulate distinct genes.

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