How genome organization influences cell fate
Study identifies how blood stem cells maintain their fate

Date:
April 29, 2022
Source:
University of California - Riverside
Summary:
Research shows how a protein complex, called chromatin assembly
factor-1, controls genome organization to maintain lineage fidelity.



FULL STORY ========================================================================== Understanding the molecular mechanisms that specify and maintain the
identities of more than 200 cell types of the human body is arguably
one of the most fundamental problems in molecular and cellular biology,
with critical implications for the treatment of human diseases. Central
to the cell fate decision process are stem cells residing within each
tissue of the body.


==========================================================================
When stem cells divide, they have the remarkable ability to choose to
self- renew -- that is, make a copy of themselves -- or mature into
defined lineages.

How a specific lineage identity is maintained every time a stem cell
divides can now be better understood thanks to the work of a team led
by biochemists at the University of California, Riverside.

The study led by Sihem Cheloufi and Jernej Murn, both assistant
professors in the Department of Biochemistry, shows how a protein
complex, called chromatin assembly factor-1, or CAF-1, controls genome organization to maintain lineage fidelity. The report appears today in
Nature Communications.

Each time a cell divides, it has to create a replica of its genome --
not only its DNA sequence but also how the DNA is packaged with proteins
into chromatin.

Chromatin is organized into genomic sites that are either open and easily accessible or more densely packed and less accessible (or closed).

"Identities of different cells rely heavily on the genome sites that are
more open because only genes located in those regions can potentially
become expressed and turned into proteins," Cheloufi explained.

She added that to maintain cell identity during cell division, the
locations of open and closed chromatin, or "chromatin organization,"
must be faithfully passed onto the new replica of the genome, a task
largely entrusted to CAF-1.



==========================================================================
"To help CAF-1 secure correct chromatin organization during cell division,
a host of transcription factors are attracted to open regions in a DNA sequence- specific manner to serve as bookmarks and recruit transcription machinery to correct lineage-specific genes, ensuring their expression,"
she said. "We wondered about the extent to which CAF-1 is required to
maintain cell-specific chromatin organization during cell division."
The authors took as a study paradigm immature blood cells that can either
self- renew or turn into neutrophils, which are non-dividing cells that
present our body's first line of defense against pathogens. Intriguingly,
they found CAF- 1 to be essential not only for maintaining the
self-renewal of these immature blood cells, but for preserving their
lineage identity. Even a moderate reduction of CAF-1 levels caused the
cells to forget their identity and adopt a mixed lineage stage.

"Neutrophil stem cells missing CAF-1 become more plastic, co-expressing
genes from different lineages, including those of red blood cells and platelets," Cheloufi said. "This is very intriguing from a developmental biology perspective." At the molecular level, the team found that
CAF-1 normally keeps specific genomic sites compacted and inaccessible
to specific transcription factors, especially one called ELF1.

"By looking at chromatin organization, we found a whole slew of genomic
sites that are aberrantly open and attract ELF1 as a result of CAF-1
loss," Murn said. "Our study further points to a key role of ELF1 in
defining the fate of several blood cell lineages." The UCR researchers
used immature blood cells derived from mouse bone marrow and engineered
for growth in tissue culture. They validated their findings in vivo using
a mouse model in collaboration with Andrew Volk, a hematology expert at
the Cincinnati Children's Hospital Medical Center and a co-corresponding
author on the study.



========================================================================== Next, Cheloufi and her colleagues would like to understand the mechanism
by which CAF-1 preserves the chromatin state at specific sites and
whether this process works differently across different cell types.

"Like a city, the genome has its landscape with specific landmarks,"
Cheloufi said. "It would be interesting to know how precisely CAF-1 and
other molecules sustain the genome's 'skyline.' Solving this problem
could also help us understand how the fate of cells could be manipulated
in a predictive manner.

Given the fundamental role of CAF-1 in packaging the genome during DNA replication, we expect it to act as a general gatekeeper of cellular
identity.

This would in principle apply to all dividing cells across numerous
tissues, such as cells of the intestine, skin, bone marrow, and even the brain." Cheloufi, Murn, and Volk were joined in the study by several UCR students, including first author Reuben Franklin, Yiming Guo, Shiyang He, Meijuan Chen, Carmen Chiem; as well as numerous collaborators among them Russell Rockne at the City of Hope, Maria Ninova at UCR, and Dr. David
Sykes and Ruslan Sadreyev at the Massachusetts General Hospital.

The study was supported by the Department of Defense, National Institutes
of Health, City of Hope/UCR biomedical research initiative, and UC cancer research coordinating committee.

The title of the research paper is "Regulation of Chromatin Accessibility
by the Histone Chaperone CAF-1 Sustains Lineage Fidelity."

========================================================================== Story Source: Materials provided by
University_of_California_-_Riverside. Original written by Iqbal
Pittalwala. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Reuben Franklin, Yiming Guo, Shiyang He, Meijuan Chen, Fei Ji,
Xinyue
Zhou, David Frankhouser, Brian T. Do, Carmen Chiem, Mihyun Jang, M.

Andres Blanco, Matthew G. Vander Heiden, Russell C. Rockne,
Maria Ninova, David B. Sykes, Konrad Hochedlinger, Rui Lu, Ruslan
I. Sadreyev, Jernej Murn, Andrew Volk, Sihem Cheloufi. Regulation of
chromatin accessibility by the histone chaperone CAF-1 sustains
lineage fidelity. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022-29730-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220429145034.htm

--- up 8 weeks, 4 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)