bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Авг. 11, 2023
Summary
During
development
cells
receive
a
variety
of
signals,
which
are
crucial
importance
to
their
fate
determination.
One
such
source
signal
is
the
Notch
signalling
pathway,
where
activity
regulates
expression
target
genes
through
core
transcription
factor
CSL.
To
understand
changes
in
behaviour
that
lead
transcriptional
active
cells,
we
have
probed
CSL
behaviours
real
time,
using
vivo
Single
Molecule
Localisation
Microscopy.
Trajectory
analysis
reveals
Notch-On
conditions
increase
fraction
bound
molecules,
but
also
proportion
molecules
with
exploratory
behaviours.
These
properties
shared
by
co-activator
Mastermind.
Furthermore,
both
and
Mastermind,
exhibit
characteristics
local
exploration
near
locus.
A
similar
observed
for
diffusing
vicinity
other
clusters.
We
suggest
therefore
acquires
an
when
part
activation
complex,
favouring
searching
retention
close
its
enhancers.
This
change
explains
how
can
efficiently
increases
occupancy
at
sites
Notch-ON
conditions.
Molecular Cell,
Год журнала:
2023,
Номер
84(2), С. 194 - 201
Опубликована: Ноя. 27, 2023
In
eukaryotic
genomes,
transcriptional
machinery
and
nucleosomes
compete
for
binding
to
DNA
sequences;
thus,
a
crucial
aspect
of
gene
regulatory
element
function
is
modulate
chromatin
accessibility
transcription
factor
(TF)
RNA
polymerase
binding.
Recent
structural
studies
have
revealed
multiple
modes
TF
engagement
with
nucleosomes,
but
how
initial
"pioneering"
results
in
steady-state
further
II
(RNAPII)
has
been
unclear.
Even
less
well
understood
distant
sites
open
interact
one
another,
such
as
when
developmental
enhancers
activate
promoters
release
RNAPII
productive
elongation.
Here,
we
review
evidence
the
centrality
conserved
SWI/SNF
family
nucleosome
remodeling
complexes,
both
pioneering
mediating
enhancer-promoter
contacts.
Consideration
unwrapping
ATP
hydrolysis
activities
together
their
architectural
features,
may
reconcile
occupancy
rapid
dynamics
observed
by
live
imaging.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 21, 2024
Pioneer
transcription
factors
(TFs)
exhibit
a
specialized
ability
to
bind
and
open
closed
chromatin,
facilitating
engagement
by
other
regulatory
involved
in
gene
activation
or
repression.
Chemical
probes
are
lacking
for
pioneer
TFs,
which
has
hindered
their
mechanistic
investigation
cells.
Here,
we
report
the
chemical
proteomic
discovery
of
electrophilic
small
molecules
that
stereoselectively
site-specifically
TF,
FOXA1,
at
cysteine
(C258)
within
forkhead
DNA-binding
domain.
We
show
these
covalent
ligands
react
with
FOXA1
DNA-dependent
manner
rapidly
remodel
its
activity
prostate
cancer
cells
reflected
redistribution
binding
across
genome
directionally
correlated
changes
chromatin
accessibility.
Motif
analysis
supports
mechanism
where
relax
canonical
DNA
preference
strengthening
interactions
suboptimal
ancillary
sequences
predicted
proximity
C258.
Our
findings
reveal
striking
plasticity
underpinning
pioneering
function
can
be
controlled
molecules.
Critical Reviews in Biochemistry and Molecular Biology,
Год журнала:
2024,
Номер
59(3-4), С. 139 - 153
Опубликована: Май 22, 2024
Chromatin
is
densely
packed
with
nucleosomes,
which
limits
the
accessibility
of
many
chromatin-associated
proteins.
Pioneer
factors
(PFs)
are
usually
viewed
as
a
special
group
sequence-specific
transcription
(TFs)
that
can
recognize
nucleosome-embedded
motifs,
invade
compact
chromatin,
and
generate
open
chromatin
regions.
Through
this
process,
PFs
initiate
cascade
events
play
key
roles
in
gene
regulation
cell
differentiation.
A
current
debate
field
if
belong
to
unique
subset
TFs
intrinsic
"pioneering
activity",
or
all
have
potential
function
within
certain
cellular
contexts.
There
also
different
views
regarding
feature(s)
define
pioneering
activity.
In
review,
we
present
evidence
from
literature
related
these
alternative
discuss
how
potentially
reconcile
them.
It
possible
both
properties,
like
tight
nucleosome
binding
structural
compatibility,
conditions,
concentration
co-factor
availability,
important
for
PF
function.
ABSTRACT
Cell
plasticity
enables
the
dynamic
changes
in
cell
identities
necessary
for
normal
development
and
tissue
repair.
Induced
reprogramming,
which
leverages
this
plasticity,
holds
great
promise
regenerative
medicine
personalized
therapies.
However,
success
of
reprogramming
is
often
impeded
by
various
molecular
barriers,
such
as
epigenetic
marks,
senescence,
activation
alternative
or
refractory
routes.
In
review,
we
examine
events
that
occur
within
between
germ
layers
adult
stem
lineages
propose
overall
similarity
pre‐existing
chromatin
accessibility
landscape
a
major
determinant
efficiency
from
one
type
to
another.
A
better
understanding
regulation
control
should
facilitate
new
methods
strategies
improve
advance
translational
research.
