UCSD. US: Two NIH Roadmap Epigenomics studies answer longstanding questions about the differences between chromosome pairs and how chromosome folding influences gene expression.
While genomics is the study of all of the genes in a cell or
organism, epigenomics is the study of all the genomic add-ons and
changes that influence gene expression but aren’t encoded in the DNA
sequence. A variety of new epigenomic information is now available in a
collection of studies published Feb. 19 in Nature by the
National Institutes of Health (NIH) Roadmap Epigenomics Program. This
information provides a valuable baseline for future studies of the
epigenome’s role in human development and disease.
Two of these studies, led by researchers at University of California,
San Diego School of Medicine and Ludwig Cancer Research, address the
differences between chromosome pairs (one inherited from mom, the other
from dad) and how chromosome folding influences gene expression.
“Both of these studies provide important considerations for
clinicians and researchers who are developing personalized medicines
based on a patient’s genomic information,” said Bing Ren, PhD, professor
of cellular and molecular medicine at UC San Diego, Ludwig Cancer
Research member and senior author of both studies.
The first paper by Ren’s group takes a look at differences in our
chromosome pairs. Each of us inherits one set from our mother and the
other from our father. Chromosome pairs are often thought to be
identical, one just a backup for the other. But this study found
widespread differences in how genes are regulated (turned on and off)
between the two chromosomes in a pair. It turns out that we all have
“biases” in our chromosomes. In other words, different traits have a
stronger contribution from one parent than the other. The study also
suggests that these biases are rooted in inherited sequence variations
and that they are not randomly distributed. These findings help explain
why, for example, all kids in a family may have their father’s hair but
their mother’s eyes.
The second paper by Ren’s group tackles how the genome is organized
and how it changes as stem cells differentiate (specialize). DNA strands
in every cell are tightly wound and folded into chromosomes. Yet
chromosomal structures, and how they influence gene expression, are not
well understood. In this study, Ren and team mapped chromosomal
structures in stem cells and several different differentiated cell types
derived from stem cells. First, they induced differentiation in the
stem cells. Then they used molecular tools to examine how the structure
of the cells’ chromosomes changed and how that change is associated with
gene activity. The team found that chromosomes are partitioned into
relatively stable structural units known as topologically associating
domains (TADs), and that TAD boundaries remain constant in different
cell types. What’s more, the researchers found that the changes in
chromosomal architecture mostly take place within the TADs in a way that
correlates with changes in the epigenome.
“The epigenome — chemical modifications to chromosomes and 3D
chromosomal structure — is not just a linear object,” Ren said. “The
epigenome is a 3D object, folded in a hierarchical way, and that should
affect how we think about many aspects of human development, health and
disease.”
Co-authors on the paper “Integrative Analysis of Haplotype-Resolved
Epigenomes Across Human Tissues” include Danny Leung, Inkyung Jung,
Nisha Rajagopal, Anthony Schmitt, Siddarth Selvaraj, Ah Young Lee,
Chia-An Yen, Yunjiang Qiu, Samantha Kuan, Lee Edsall, Ludwig Cancer
Research; Shin Lin, Yiing Lin, Stanford University and Washington
University School of Medicine; Wei Xie, formerly at Ludwig Cancer
Research and now at Tsinghua University; Feng Yue, formerly at Ludwig
Cancer Research and now at Pennsylvania State University; Manoj
Hariharan, Joseph R. Ecker, Howard Hughes Medical Institute and Salk
Institute for Biological Studies; Pradipta Ray, University of Texas;
Hongbo Yang, Neil C. Chi, UC San Diego; and Michael Q. Zhang, University
of Texas, Dallas and Tsinghua University.
Co-authors on the paper “Chromatin Architecture Reorganization during
Stem Cell Differentiation” include Jesse R. Dixon, Siddarth Selvaraj,
Ludwig Cancer Research and UC San Diego; Inkyung Jung, Yin Shen, Ah
Young Lee, Zhen Ye, Audrey Kim, Nisha Rajagopal, Yarui Diao, Ludwig
Cancer Research; Jessica E. Antosiewicz-Bourget, Morgridge Institute for
Research; Wei Xie, Tsinghua University; Jing Liang, Huimin Zhao,
University of Illinois at Urbana-Champaign; Victor V. Lobanenkov,
National Institute of Allergy and Infectious Diseases; Joseph R. Ecker,
Howard Hughes Medical Institute and Salk Institute for Biological
Studies; James Thomson, Morgridge Institute for Research, University of
Wisconsin and University of California, Santa Barbara.
These studies were funded, in part, by the NIH Roadmap Epigenomics
Program (U01ES017166), the California Institute for Regenerative
Medicine and Ludwig Cancer Research.