Illuminating dark matter in human DNA

Date:
November 13, 2021
Source:
University of California - San Diego
Summary:
Researchers have produced a single-cell chromatin atlas for the
human genome. Delineating chromatin regions in cells of different
human tissue types would be a major step toward understanding the
role of gene regulatory elements (non-coding DNA) in human health
or disease.



FULL STORY ========================================================================== Researchers at University of California San Diego have produced a
single-cell chromatin atlas for the human genome. Chromatin is a complex
of DNA and protein found in eukaryotic cells; regions of chromatin at key
gene regulatory elements appear in open configurations within certain
cell nuclei. Precisely delineating these accessible chromatin regions
in cells of different human tissue types would be a major step toward understanding the role of gene regulatory elements (non-coding DNA)
in human health or disease.


==========================================================================
The findings are published online in the November 12, 2021, issue of Cell.

For scientists, the human genome, popularly called the "book of life,"
is mostly unwritten. Or at least unread. While science has famously put
an (approximate) number to all of the protein-coding genes required to
build a human being, approximately 20,000+, that estimation does not
really begin to explain how exactly the construction process works or,
in the case of disease, it might go awry.

"The human genome was sequenced 20 years ago, but interpreting the
meaning of this book of life continues to be challenging," said Bing Ren,
PhD, director of the Center for Epigenomics, professor of cellular and molecular medicine at UC San Diego School of Medicine and a member of
the Ludwig Institute for Cancer Research at UC San Diego.

"A major reason is that the majority of the human DNA sequence, more than
98 percent, is non-protein-coding, and we do not yet have a genetic
code book to unlock the information embedded in these sequences."
Put another way, it's a bit like knowing chapter titles but with the
rest of the pages still blank.



========================================================================== Efforts to fill in the blanks are broadly captured in an ongoing
international effort called the Encyclopedia of DNA Elements (ENCODE),
and include the work of Ren and colleagues. In particular, they have investigated the role and function of chromatin, a complex of DNA and
proteins that form chromosomes within the nuclei of eukaryotic cells.

DNA carries the cell's genetic instructions. The major proteins in
chromatin, called histones, help tightly package the DNA in a compact
form that fits within the cell nucleus. (There are roughly six feet of
DNA tucked into each cell nucleus and approximately 10 billion miles in
each human body.) Changes in how chromatin bundles up DNA are associated
with DNA replication and gene expression.

After working with mice, Ren and collaborators turned their attention
to a single-cell atlas of chromatin in the human genome.

They applied assays to more than 600,000 human cells sampled from 30
adult human tissue types from multiple donors, then integrated that
information with similar data from 15 fetal tissue types to reveal the
status of chromatin at approximately 1.2 million candidate cis-regulatory elements in 222 distinct cell types.

"One of the initial challenges was identifying the best experimental
conditions for such a diverse set of sample types, particularly given
each tissue's unique makeup and sensitivity to homogenization," said
study co-author Sebastian Preissl, PhD, associate director for Single
Cell Genomics at UC San Diego Center for Epigenomics, a collaborative
research center that carried out the assays.



========================================================================== Cis-regulatory elements are regions of non-coding DNA that regulate transcription (copying a segment of DNA into RNA) of neighboring genes.

Transcription is the essential process that converts genetic information
into action.

"Studies in the last decade have established that sequence variations in
non- coding DNA are a key driver in multi-genic traits and diseases in
human populations, such as diabetes, Alzheimer's' disease and autoimmune diseases," said study co-author Kyle J. Gaulton, PhD, assistant professor
in the Department of Pediatrics at UC San Diego School of Medicine.

"A new paradigm that helps explain how these noncoding variants contribute
to diseases posits that these sequence alterations disrupt function of transcriptional regulatory elements and lead to dysregulation of gene expression in disease-relevant cell types, such as neurons, immune cells
or epithelial cells," said co-first author Kai Zhang, PhD, a postdoctoral fellow in the Department of Cellular and Molecular Medicine. "A major
barrier to unlocking the function of noncoding risk variants, however,
is the lack of cell-type-specific maps of transcriptional regulatory
elements in the human genome." Ren said the new findings identify disease-trait-relevant cell types for 240 multi-genic traits and diseases,
and annotate the risk of noncoding variants.

"We believe that this resource will greatly facilitate the study of
mechanism across a broad spectrum of human diseases for many years to
come." Preissl said the chromatin atlas will also allow the scientific community to unravel tissue environment-specific differences of cell
types that reside in multiple tissues, such as fibroblasts, immune cells
or endothelial cells.

Co-authors include: James D. Hocker and Yang E. Li, Ludwig Institute
for Cancer Research and UC San Diego; Michael Miller, Hiaomeng Hou,
Joshua Chiou, Olivier B. Poirion and Allen Wang, all at UC San Diego;
and Yunjiang Qiu, Ludwig Institute for Cancer Research, La Jolla.

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Scott La
Fee. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kai Zhang, James D. Hocker, Michael Miller, Xiaomeng Hou, Joshua
Chiou,
Olivier B. Poirion, Yunjiang Qiu, Yang E. Li, Kyle J. Gaulton,
Allen Wang, Sebastian Preissl, Bing Ren. A single-cell atlas of
chromatin accessibility in the human genome. Cell, 2021; DOI:
10.1016/ j.cell.2021.10.024 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211113072254.htm

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