In an unprecedented atlas, researchers begin to map how genes are
turned on or off in different cells, a step toward better understanding the
connections between genetics and disease.
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.
Reference:
A single-cell atlas of chromatin accessibility in the human genome by 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 and Bing Ren, 12 November 2021, Cell.
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