Nuclear receptor-enhanced transcription requires motor- and LSD1-dependent gene networking in interchromatin granules.
While the transcriptional machinery has been extensively dissected at the molecular level, little is known about regulation of chromosomal organization in the three-dimensional space of the nucleus to achieve integrated transcriptional responses to diverse signaling events. Here, we report that ligand induces rapid interchromosomal interactions among subsets of estrogen receptor alpha-bound transcription units, with a dramatic reorganization of nuclear territories requiring nuclear actin/myosin-I transport machinery, dynein light chain 1 (DLC1), and a specific subset of transcriptional coactivators and chromatin remodeling complexes. We establish a requirement for the histone lysine demethylase, LSD1, in directing specific interchromosomal interaction loci to distinct interchromatin granules, long thought to be "storage" sites for splicing machinery, and demonstrate that these three-dimensional motor-dependent interactions are required to achieve enhanced transcription of specific estrogen-receptor target genes. These findings reveal roles for the modulation of nuclear architecture in orchestrating regulated gene-expression programs in the mammalian nucleus.
Nunez
Esperanza
E
Howard Hughes Medical Institute, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA.
Kwon
Young-Soo
YS
Hutt
Kasey R
KR
Hu
Qidong
Q
Cardamone
Maria Dafne
MD
Ohgi
Kenneth A
KA
Garcia-Bassets
Ivan
I
Rose
David W
DW
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
Fu
Xiang-Dong
XD
D000199:Actins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D053263:Gene Regulatory Networks; D056466:Histone Demethylases; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D014158:Transcription, Genetic
D000199:Actins; D002843:Chromatin; D047628:Estrogen Receptor alpha; D020409:Molecular Motor Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating