A molecular glue for turning on human cell pluripotency

Date:
April 28, 2022
Source:
Baylor College of Medicine
Summary:
Researchers report insights into the mechanism of how human NANOG
facilitates the activation of cell pluripotency.



FULL STORY ========================================================================== There are cells in the body known as pluripotent stem cells that are
yet to specialize in a particular biological function. These cells
maintain the potential to become any of the possible cell types in an
organism. Pluripotent stem cells have shown great promise in fields
such as regenerative and transplant medicine for their properties,
including unlimited self-renewal. The protein NANOG is the telltale
marker of pluripotent stem cells and a necessary ingredient to reset specialized cells back into nai"ve, untrained stem cells.

How human NANOG accomplishes this feat remains largely a mystery.


========================================================================== Researchers at Baylor College of Medicine and collaborating institutions
report in the journal Nature Cell Biology insights into the mechanism
of how human NANOG facilitates the activation of cell pluripotency. The
team discovered that NANOG's 'super stickiness' enables it to form large aggregates at very low concentrations. These aggregates interact with
chromatin -- strings of DNA and proteins that coil to form chromosomes
carrying the cells' genetic information -- to reshape the genomic
landscape in a way that activates a pluripotent state.

"Resetting specialized cells to a pluripotent state requires massive reorganization of the chromatin and changes in gene expression -- turning
on genes involved in pluripotency and turning off genes that specify specialized cells," said corresponding author Dr. Josephine Ferreon,
assistant professor of pharmacology and chemical biology and member of
the Dan L Duncan Comprehensive Cancer Center at Baylor. "Furthermore, coordinated gene activation often requires bringing DNA elements that
are far apart closer to enable gene expression. We found that NANOG's properties -- its naturally floppy, flexible 3D shape and a C-terminal
tail that is structurally akin to prion-like proteins -- enable it to
achieve this." Studying NANOG poses significant challenges NANOG's high tendency to self-adhere and aggregate poses a problem for traditional
ensemble techniques that require high protein concentrations. To study
this very challenging protein, the team resorted to highly sensitive fluorescence approaches.

"In this study, we applied single molecule and fluorescence fluctuation microscopy techniques with which we can visualize whether two molecules interact with each other. The experiments were performed at very small concentrations, picomolar to nanomolar, where we can usually avoid
aggregation and investigate highly aggregation-prone proteins," said co-corresponding author Dr. Allan Chris Ferreon, assistant professor of pharmacology and chemical biology at Baylor. "However, with NANOG, even at extremely low concentrations, we still detected aggregation. Nonetheless,
we were able to show that NANOG aggregation is actually essential to
its function as a master transcription factor and a mediator of the
bridging of DNAs. This phenomenon may be unique to NANOG." "We think
that this phenomenon is the reason why NANOG expression is key to the establishment of pluripotency. When NANOG's level is low, cells are prone
to differentiate, and when its level is high, the ground pluripotent state
or 'full reset' is achieved and maintained," Dr. Josephine Ferreon said.

NANOG aggregates are similar to those of amyloids, which are culpable
for Alzheimer's disease and other neurodegenerative disorders. However,
in NANOG's case, the aggregates are not associated with a harmful
condition, but with an essential cellular process, the activation
of cell pluripotency. A growing body of scientific evidence suggests
that not all amyloids are harmful, some can be rather functional. More
and more of these amyloid-forming prion-like proteins are found to
be molecular players of cellular functions such as gene expression,
chromatin condensation and cell signaling.

The researchers think that NANOG acts like a molecular glue that can
initiate and stabilize key chromatin interactions important for the
pluripotent state.

NANOG's aggregation behavior also explains its role as a molecular 'hub' protein and its interactions with many important chromatin regulators
that are involved in opening chromatin and recognizing and modifying
specific chromatin regions.

"In the future, we hope to understand more about the role of NANOG
and its prion-like region in recruiting or cooperating with important transcription factors, coactivators and epigenetic modulators to reshape
the genomic landscape," Dr. Josephine Ferreon said.

Other contributors to this work include Kyoung-Jae Choi, My Diem Quan,
Chuangye Qi, Joo-Hyung Lee, Phoebe S. Tsoi, Mahla Zahabiyon, Aleksandar
Bajic, Liya Hu, B. V. Venkataram Prasad, Shih-Chu Jeff Liao and Wenbo Li.

This work was supported by an NIGMS, NIH grant (R01 GM122763), NINDS,
NIH grant (R01 NS105874, R21 NS107792 and R21 NS109678) and a Cancer
Prevention and Research Institute of Texas (CPRIT) Scholarship. Part of
this work is supported by the NIH ''4D Nucleome'' program (U01HL156059),
NIGMS (R21GM132778, R01GM136922), CPRIT (RR160083, CPRIT RP180734),
the Welch foundation (AU-2000- 20190330) and UTHealth Innovation for
Cancer Prevention Research Training Program Postdoctoral Fellowship
(CPRIT RP210042). Further support was provided by the Eunice Kennedy
Shriver National Institute of Child Health & Human Development of the
National Institutes of Health under award number P50HD103555.


========================================================================== Story Source: Materials provided by Baylor_College_of_Medicine. Original written by Molly Chiu. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kyoung-Jae Choi, My Diem Quan, Chuangye Qi, Joo-Hyung Lee, Phoebe S.

Tsoi, Mahla Zahabiyon, Aleksandar Bajic, Liya Hu, B. V. Venkataram
Prasad, Shih-Chu Jeff Liao, Wenbo Li, Allan Chris M. Ferreon,
Josephine C. Ferreon. NANOG prion-like assembly mediates
DNA bridging to facilitate chromatin reorganization and
activation of pluripotency. Nature Cell Biology, 2022; DOI:
10.1038/s41556-022-00896-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220428125411.htm

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