Epigenetic landscape modulates pioneer transcription factor binding


Date:
May 24, 2023
Source:
St. Jude Children's Research Hospital
Summary:
Scientists studied how the epigenetic landscape influences the
binding of pioneer transcription factors, affecting access to DNA.


Facebook Twitter Pinterest LinkedIN Email

==========================================================================
FULL STORY ==========================================================================
Like thread tightly wrapped around a spool, DNA is wrapped around histones
and packaged into structures called nucleosomes. Scientists at St. Jude Children's Research Hospital are exploring how a type of transcription
factor called a pioneer transcription factor accesses DNA even when
it is tightly wound. Their work revealed how the epigenetic landscape influences transcription factor binding. Problems with transcription have
been implicated in numerous cancers, so this more detailed understanding
of the process may aid in developing future therapeutics. The study was published today in Nature.

The nucleosome packaging of DNA can physically block transcription
factors that regulate gene expression from accessing their binding
sites. Restricting access to DNA is an integral part of how transcription
is regulated. However, pioneer transcription factors can bind to their
target piece of DNA even within compacted chromatin and are also known
to promote the binding of other transcription factors.

Among pioneer transcription factors are the so-called Yamanaka factors
which include Oct4 and are used to induce pluripotency (the ability to
give rise to different cell types). How pioneer transcription factors
access tightly wound DNA was unclear. To better understand the process, scientists at St. Jude used cryo-electron microscopy (cryo-EM) and
biochemistry to investigate how Oct4 interacts with nucleosomes.

"Building on prior work to understand the dynamic behavior of nucleosomes,
we wanted to understand how other factors might utilize those dynamic
changes to access chromatin," said corresponding author Mario Halic,
Ph.D., St.

Jude?Department of Structural Biology. "Oct4 did not bind where we
anticipated it might -- rather than binding inside the nucleosome, we
found that it bound a little bit outside." "One of the main findings is
that epigenetic modifications can affect transcription factor binding
and cooperativity," Halic added. "The existing epigenetic state of
chromatin can determine how transcription factors will cooperatively bind
to chromatin." The epigenetic impact Results show that the first Oct4
molecule binding "fixes" the nucleosome in a position that increases
the exposure of other binding sites, thus promoting the binding of
additional transcription factors and explaining transcription factor cooperativity.?They also found that Oct4 contacts histones, and these interactions promote chromatin opening and influence cooperativity. Their
work also showed that modifications at histone H3K27 affect the
positioning of DNA by Oct4. These findings explain how the epigenetic
landscape can regulate Oct4 activity to ensure proper cell programming.

Notably, the researchers used endogenous human DNA sequences instead of artificial sequences to assemble their nucleosomes. This allowed them
to study the dynamic nature of the nucleosome, despite it being more challenging to work with.

"In this work, we used real genomic DNA sequences to study transcription factors in the context of where they function," said first author Kalyan
Sinha, Ph.D., St. Jude Department of Structural Biology. "This strategy
allowed us to discover that the first binding event of Oct4 positions
the nucleosomal DNA in a manner that allows cooperative binding of
additional Oct4 molecules to internal sites. In addition, we observed
exciting interactions with histone tails and have seen that histone modifications can alter those interactions.

Together, these findings provide new insights into the pioneering
activity of Oct4." "Histone modifications affect how DNA is positioned
and how transcription factors can bind cooperatively," Sinha added,
"which means in cells, if you have the same DNA sequence, different
epigenetic modifications can result in different, combinatorial effects
on transcription factor binding."
* RELATED_TOPICS
o Health_&_Medicine
# Epigenetics # Human_Biology # Genes # Workplace_Health
# Amyotrophic_Lateral_Sclerosis # Nervous_System #
Multiple_Sclerosis_Research # Forensics
* RELATED_TERMS
o DNA_microarray o Fetus o DNA_repair o Epidemiology o
Introduction_to_genetics o DNA o Genetically_modified_organism
o Trait_(biology)

========================================================================== Story Source: Materials provided by
St._Jude_Children's_Research_Hospital. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Kalyan K. Sinha, Silvija Bilokapic, Yongming Du, Deepshikha Malik,
Mario
Halic. Histone modifications regulate pioneer transcription factor
cooperativity. Nature, 2023; DOI: 10.1038/s41586-023-06112-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230524182037.htm

--- up 1 year, 12 weeks, 2 days, 10 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)