Chromatin organization and transcription regulations

Chromatin packages eukaryotic genomes via a hierarchical series of folding steps, encrypting multiple layers of genetic and epigenetic information such as histone modifications and 3D chromatin organization, which are capable of regulating nuclear transactions in response to complex environmental signals and cellular state transitions. Structural analysis of chromosome folding has been revolutionized by the Chromosome Conformation Capture (3C) family of techniques via measuring relative contact frequency between pairs of genomic loci in vivo. The 3C-based assays have revealed many chromosomal features relevant to various biological systems and disorder models such as the scale of full chromosomal territories, active and inactive compartments, topologically-associating domains (TADs), and long-range chromatin loops (also known as CTCF-Cohesin loops). To push the edge of detection limit, we developed an innovative 3C-based method called Micro-C for the mammalian systems, which enables nucleosome-resolution maps of chromatin folding, achieving by using micrococcal nuclease (MNase) to fragment genome into mononucleosomes prior to the proximity ligation step. The method thus serves as a standalone technique to discover bona fide and de novo enhancer-promoter contacts and fine chromatin folding at sub-kb scale. The streamlined protocol also provides a single experiment that enables analysis of chromosome folding at all biologically-relevant length with unprecedented sensitivity and resolution.

Current key focus:

  • How do transcription per se and transcription factors shape the 3D genome?
  • How is chromatin being reorganized during cell-type transition?
  • Developing computational approaches to identify enhancer-promoter links from Micro-C data.

Figure: Micro-C sees ALL.

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Stanley Hsieh