Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.

Gryder, B.e., Wu, L., Woldemichael, G.m., Pomella, S., Quinn, T.r., Park, P., et al. (2019). Chemical genomics reveals histone deacetylases are required for core regulatory transcription. NATURE COMMUNICATIONS, 10, 1-12 [10.1038/s41467-019-11046-7].

Chemical genomics reveals histone deacetylases are required for core regulatory transcription

Pomella, S.;
2019-01-01

Abstract

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/05
English
Gryder, B.e., Wu, L., Woldemichael, G.m., Pomella, S., Quinn, T.r., Park, P., et al. (2019). Chemical genomics reveals histone deacetylases are required for core regulatory transcription. NATURE COMMUNICATIONS, 10, 1-12 [10.1038/s41467-019-11046-7].
Gryder, Be; Wu, L; Woldemichael, Gm; Pomella, S; Quinn, Tr; Park, Pmc; Cleveland, A; Stanton, Bz; Song, Y; Rota, R; Wiest, O; Yohe, Me; Shern, Jf; Qi, J; Khan, J
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/311778
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