Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA polymerase II productive elongation
Karen G. Cornejo,
Andie Venegas,
Morgan H. Sono,
Madeline Door,
Brenda Gutierrez-Ruiz,
Lucy B. Karabedian,
Supratik G. Nandi,
Marco Hadisurya,
W. Andy Tao,
Emily C. Dykhuizen,
Ramendra N. Saha
Affiliations
Karen G. Cornejo
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Andie Venegas
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Morgan H. Sono
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Madeline Door
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Brenda Gutierrez-Ruiz
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Lucy B. Karabedian
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Supratik G. Nandi
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA
Marco Hadisurya
Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA
W. Andy Tao
Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Purdue University Institute for Cancer Research, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Emily C. Dykhuizen
Purdue University Institute for Cancer Research, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Ramendra N. Saha
Molecular and Cell Biology Department, School of Natural Sciences, University of California, Merced, 5200 North Lake Road, Merced, CA 95343, USA; Corresponding author
Summary: Signal-dependent RNA polymerase II (RNA Pol II) productive elongation is an integral component of gene transcription, including that of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating RNA Pol II overcomes nucleosomal barriers. Using RNAi, three degraders, and several small-molecule inhibitors, we show that the mammalian switch/sucrose non-fermentable (SWI/SNF) complex of neurons (neuronal BRG1/BRM-associated factor or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal RNA Pol II pausing and signal-dependent RNA Pol II recruitment (loading) and, importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent RNA Pol II. Mechanistically, RNA Pol II elongation is mediated by activity-induced nBAF assembly (especially ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of RNA Pol II transcription and reveal mechanisms underlying activity-induced RNA Pol II elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.
