Research Roundup

"Motors bring genes together".

Richard Robinson
rrobinson@nasw.org

Nuclear motors rearrange chromosomes to enhance estrogen-driven transcription, according to Esperanza Nunez, Michael Rosenfeld, Xiang-Dong Fu (University of California at San Diego, CA), and colleagues.

Estrogen-responsive enhancers occur throughout the genome, often long distances from the genes whose transcription they enhance. To determine how these enhancers and their bound estrogen receptors are brought to their gene targets, the authors used FISH to follow their movements. Under the influence of estrogen, two genes on chromosomes 2 and 21 formed 2–21 pairs or tetrads of all four alleles. The team never observed 2–2 or 21–21 pairings. The factors that cause these specific pairings, and prevent others, are unknown.

Genes on chromosome 2 (red) and 21 (green) come together in the presence of estrogen (bottom).

Other estrogen-regulated gene sets converged in other nuclear locations, each the site of an RNA-processing nuclear speckle. When the authors knocked down a demethylase that is required for estrogen-dependent gene activation, genes came together but did not bind to the speckle. Gene expression from interacting alleles was much higher than for noninteracting ones, indicating that their linkages increase transcription rates. JCB

"Nuclear Receptor-Enhanced Transcription Requires Motor- and LSD1-Dependent Gene Networking in Interchromatin Granules".

Esperanza Nunez ^{1, 2, 7}, Young-Soo Kwon ^{4, 7}, Kasey R. Hutt ^{1, 5}, Qidong Hu ¹, Maria Dafne Cardamone ^{1, 6}, Kenneth A. Ohgi ¹, Ivan Garcia-Bassets ¹, David W. Rose ³, Christopher K. Glass ⁴, Michael G. Rosenfeld ^{1, *}, and Xiang-Dong Fu ^{3, *},

¹ Howard Hughes Medical Institute, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
² Biomedical Sciences Graduate Program, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
³ Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
⁴ Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
⁵ Bioinformatics Graduate Program, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0651, USA
⁶ Department of Oncological Sciences, University of Turin, Turin, Italy
⁷ These two authors contributed equally to this work.

^@ Corresponding author: Michael G. Rosenfeld  mrosenfeld@ucsd.edu
^@ Corresponding author: Xiang-Dong Fu  xdfu@ucsd.edu

Summary:

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 a-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.

In this beautiful study by Esperanza Nunez, Young-Soo Kwon,  Kasey R. Hutt, Qidong Hu, Maria Dafne Cardamone, Kenneth A. Ohgi, Ivan Garcia-Bassets, David W. Rose, Christopher K. Glass, Michael G. Rosenfeld,, and Xiang-Dong Fu, it is shown that actively-bound estrogen is required to enhance Kissing Chromosomes between the separate receptor sites for such estrogens. It is further shown that such interchromosomal activity requires nuclear actinomysin-1 transport machinery, dynein light chain 1, and a specific subset of transcriptional coactivators and chromatin remodeling complexes. The products of such complex transcription may be paired sense-antisense RNA species from a DNA-DNA tetraplex site.

Links to Euchromatin Activator RNA Reviews:
Links to Euchromatin Activator RNA Research:
Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:
Links to Selective Gene Transcription:
Links to RNA-Induced Epigenetics:
Links to RNA-Induced Embryogenesis:
Links to RNA and Biological Causality:
Links to Reprogramming and Neoplasia:

A Brief History of Activator RNA:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA". (PowerPoint Presentation).