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November 22, 2017

Gene interactions and positions in the nucleus determine cell identity

CiRA scientists report a new technology, ms4C-seq, that shows how gene interactions and gene translocations in the nucleus are coordinated during cell reprogramming.

To successfully reprogram cells into iPS cells, a series of nuclear events must occur. Among these is the movement of specific genes from the nuclear membrane to the nuclear interior. In a new study seen in Nature Communication, the Takuya Yamamoto lab describes new technology, ms4C-seq, and uses it to show the translocation of these genes is accompanied by an increase in their interaction with other genes. The study gives important insights on the genetic structural and spatial changes necessary for cell reprogramming.

"Bivalent domains are regions in a gene that have active and repressive marks for transcription. They mark genes that are silent but poised to undergo transcription rapidly," explains Hiroki Ikeda, the member of the Yamamoto lab who wrote the study.

The maintenance and differentiation of iPS cells depends on the regulation of bivalent genes. Ikeda reasoned that much like the morphological and functional changes that occur in a cell during reprogramming, bivalent genes too undergo structural and spatial changes when cells are reprogrammed.

"Chromatin interactions regulate gene expressions. If a gene interacts with repressor regions it is repressed. If a gene interacts with an activator region it is activated," he continued.

Using public data, the study shows that bivalent genes move from the nuclear membrane to the nuclear interior during reprogramming. Ikeda considered whether this nuclear translocation is accompanied by changes in chromatin interactions between bivalent genes. To study the interactions, the lab reports ms4C, which is a modified version of standard chromatin conformation capture (CCC) technology. ms4C lowers both the amount of DNA needed to study multiple interaction sites and the noise in the signal to enhance detection of chromatin interactions.

Comparisons of the public data and ms4C data revealed that as bivalent genes translocate from the nuclear periphery to the nuclear interior during reprogramming, their interactions with each other increases.

Yamamoto believes that change in the nuclear position from the periphery to the interior during reprogramming provides the transcription machinery easy access to bivalent genes.

"The changes in interactions with nuclear translocation may open interaction sites between bivalent genes for rapid response to extracellular differentiation cues," he said.

Paper Details
  • Journal: Nature Communications
  • Title: Structural and spatial chromatin features at developmental gene loci in human pluripotent stem cells
  • Authors: Hiroki Ikeda1, Masamitsu Sone1,2, Shinya Yamanaka1,3, and Takuya Yamamoto1, 2, 4
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan
    3. Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA
    4. AMED-CREST, AMED 1-7-1 Otemach, Chiyodaku, Tokyo 100-0004, Japan.
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