Molecular Systems Biology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 31, 2025
Abstract
The
general
transcription
machinery
and
its
occupancy
at
promoters
are
highly
conserved
across
metazoans.
This
contrasts
with
the
kinetics
of
mRNA
production
that
considerably
differ
between
model
species
such
as
Drosophila
mouse.
molecular
basis
for
these
kinetic
differences
is
currently
unknown.
Here,
we
used
Single-Molecule
Footprinting
to
measure
RNA
Polymerase
II
(Pol
II)
occupancy,
fraction
DNA
molecules
bound,
in
mouse
cell
lines.
Single-molecule
data
reveals
Pol
on
average
3–5
times
more
frequent
transcriptionally
active
than
promoters.
Kinetic
modelling
states
suggests
determined
by
ratio
initiation
turnover
rates.
We
chemical
perturbation
determine
rate
both
species.
Integration
into
shows
infrequent
explained
combination
high
low
Nature Structural & Molecular Biology,
Journal Year:
2024,
Volume and Issue:
31(3), P. 498 - 512
Published: Jan. 5, 2024
Abstract
Three-dimensional
(3D)
epigenome
remodeling
is
an
important
mechanism
of
gene
deregulation
in
cancer.
However,
its
potential
as
a
target
to
counteract
therapy
resistance
remains
largely
unaddressed.
Here,
we
show
that
epigenetic
with
decitabine
(5-Aza-mC)
suppresses
tumor
growth
xenograft
models
pre-clinical
metastatic
estrogen
receptor
positive
(ER+)
breast
tumor.
Decitabine-induced
genome-wide
DNA
hypomethylation
results
large-scale
3D
deregulation,
including
de-compaction
higher-order
chromatin
structure
and
loss
boundary
insulation
topologically
associated
domains.
Significant
associates
ectopic
activation
ER-enhancers,
gain
ER
binding,
creation
new
enhancer–promoter
interactions
concordant
up-regulation
ER-mediated
transcription
pathways.
Importantly,
long-term
withdrawal
partially
restores
methylation
at
ER-enhancer
elements,
resulting
repression.
Our
study
illustrates
the
ER+
endocrine-resistant
cancer
by
methylation-dependent
rewiring
interactions,
which
are
suppression
growth.
Cellular and Molecular Life Sciences,
Journal Year:
2024,
Volume and Issue:
81(1)
Published: April 11, 2024
Abstract
The
epigenome—the
chemical
modifications
and
chromatin-related
packaging
of
the
genome—enables
same
genetic
template
to
be
activated
or
repressed
in
different
cellular
settings.
This
multi-layered
mechanism
facilitates
cell-type
specific
function
by
setting
local
sequence
3D
interactive
activity
level.
Gene
transcription
is
further
modulated
through
interplay
with
factors
co-regulators.
human
body
requires
this
epigenomic
apparatus
precisely
installed
throughout
development
then
adequately
maintained
during
lifespan.
causal
role
epigenome
pathology,
beyond
imprinting
disorders
tumour
suppressor
genes,
was
brought
into
spotlight
large-scale
sequencing
projects
identifying
that
mutations
machinery
genes
could
critical
drivers
both
cancer
developmental
disorders.
Abrogation
providing
new
molecular
insights
pathogenesis.
However,
deciphering
full
breadth
implications
these
changes
remains
challenging.
Knowledge
accruing
regarding
disease
mechanisms
clinical
biomarkers,
pathogenically
relevant
surrogate
tissue
analyses,
respectively.
Advances
include
consortia
generated
reference
epigenomes,
high-throughput
DNA
methylome
association
studies,
as
well
ageing-related
diseases
from
biological
‘clocks’
constructed
machine
learning
algorithms.
Also,
3rd-generation
beginning
disentangle
complexity
modification
haplotypes.
Cell-free
methylation
a
biomarker
has
clear
utility
potential
assess
organ
damage
across
many
Finally,
understanding
aetiology
brings
it
opportunity
for
exact
therapeutic
alteration
CRISPR-activation
inhibition.
Proceedings of the National Academy of Sciences,
Journal Year:
2024,
Volume and Issue:
121(11)
Published: March 5, 2024
The
early-life
environment
can
profoundly
shape
the
trajectory
of
an
animal's
life,
even
years
or
decades
later.
One
mechanism
proposed
to
contribute
these
effects
is
DNA
methylation.
However,
frequency
and
functional
importance
methylation
in
shaping
on
adult
outcomes
poorly
understood,
especially
natural
populations.
Here,
we
integrate
prospectively
collected
data
fitness-associated
variation
early
with
estimates
at
477,270
CpG
sites
256
wild
baboons.
We
find
highly
heterogeneous
relationships
between
adulthood:
aspects
linked
resource
limitation
(e.g.,
low-quality
habitat,
drought)
are
associated
many
more
than
other
types
environmental
stressors
low
maternal
social
status).
Sites
enriched
gene
bodies
putative
enhancers,
suggesting
they
functionally
relevant.
Indeed,
by
deploying
a
baboon-specific,
massively
parallel
reporter
assay,
show
that
subset
windows
containing
capable
regulatory
activity,
that,
for
88%
drought-associated
windows,
enhancer
activity
methylation-dependent.
Together,
our
results
support
idea
patterns
contain
persistent
signature
environment.
also
indicate
not
all
exposures
leave
equivalent
mark
suggest
socioenvironmental
time
sampling
likely
be
important.
Thus,
multiple
mechanisms
must
converge
explain
fitness-related
traits.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 22, 2025
We
present
a
genome-scale
method
to
map
the
single-molecule
co-occupancy
of
structurally
distinct
nucleosomes,
subnucleosomes,
and
other
protein-DNA
interactions
via
long-read
high-resolution
adenine
methyltransferase
footprinting.
I
teratively
D
efined
L
engths
Inaccessibility
(IDLI)
classifies
nucleosomes
on
basis
shared
patterns
intranucleosomal
accessibility,
into:
i.)
minimally-accessible
chromatosomes;
ii.)
octasomes
with
stereotyped
DNA
accessibility
from
superhelical
locations
(SHLs)
±1
through
±7;
iii.)
highly-accessible
unwrapped
nucleosomes;
iv.)
subnucleosomal
species,
such
as
hexasomes,
tetrasomes,
short
protections.
Applying
IDLI
mouse
embryonic
stem
cell
(mESC)
chromatin,
we
discover
widespread
nucleosomal
distortion
individual
mammalian
chromatin
fibers,
>85%
surveyed
displaying
degrees
intranucleosomally
accessible
DNA.
observe
epigenomic-domain-specific
distorted
nucleosome
positioning,
including
at
enhancers,
promoters,
satellite
repeat
sequences.
Nucleosome
is
programmed
by
presence
bound
transcription
factors
(TFs)
cognate
motifs;
occupied
TF
binding
sites
are
differentially
decorated
compared
unbound
sites,
degradation
experiments
establish
direct
roles
for
TFs
in
structuring
binding-site
proximal
nucleosomes.
Finally,
apply
context
primary
hepatocytes,
observing
evidence
pervasive
vivo.
Further
genetic
reveal
role
hepatocyte
master
regulator
FOXA2
directly
impacting
hepatocyte-specific
regulatory
elements
vivo
.
Our
work
suggests
extreme-but
regulated-plasticity
level.
Further,
our
study
offers
an
essential
new
framework
model
factor
binding,
remodeling,
cell-type
specific
gene
regulation
across
biological
contexts.
Nucleic Acids Research,
Journal Year:
2023,
Volume and Issue:
51(16), P. 8480 - 8495
Published: July 24, 2023
Transcription
factors
(TFs)
are
proteins
that
affect
gene
expression
by
binding
to
regulatory
regions
of
DNA
in
a
sequence
specific
manner.
The
TFs
is
controlled
many
factors,
including
the
sequence,
concentration
TF,
chromatin
accessibility
and
co-factors.
Here,
we
systematically
investigated
mechanism
hundreds
analysing
ChIP-seq
data
with
our
explainable
statistical
model,
ChIPanalyser.
This
tool
uses
as
inputs
motif;
capacity
distinguish
between
strong
weak
sites;
TF;
accessibility.
We
found
approximately
one
third
predicted
bind
genome
independent
fashion,
which
includes
can
open
chromatin,
their
co-factors
similar
motifs.
Our
model
this
be
case
when
TF
binds
its
strongest
genome,
only
small
number
have
dense
at
weakest
regions,
such
CTCF,
USF2
CEBPB.
study
demonstrated
human
mouse
ChIPanalyser
high
accuracy
showed
chromatin.
