Here,
we
investigated
the
potential
interaction
between
bromodomain-containing
protein
4
(BRD4),
an
established
epigenetic
modulator
and
transcriptional
coactivator,
p63,
a
member
of
p53
transcription
factor
family,
essential
for
epithelial
development
skin
homeostasis.
Our
protein–protein
assays
demonstrated
strong
conserved
physical
BRD4
family
members—p63,
p73,
p53—suggesting
shared
binding
region
among
these
proteins.
While
role
in
cancer
through
its
with
has
been
explored,
effects
Bromodomain
Extra
Terminal
(BET)
inhibitors
non-transformed
cells,
such
as
keratinocytes,
remain
largely
unknown.
functional
analyses
revealed
changes
cellular
proliferation
differentiation
keratinocytes
depleted
either
p63
or
BRD4,
which
were
further
supported
by
using
inhibitor
JQ1.
Transcriptomic
analyses,
chromatin
immunoprecipitation,
RT-qPCR
indicated
synergistic
mechanism
regulating
keratinocyte-specific
target
genes,
including
HK2,
FOXM1,
EVPL.
This
study
not
only
highlights
complex
relationship
members
but
also
suggests
maintaining
keratinocyte
functions.
findings
pave
way
exploration
therapeutic
applications
treating
disorders.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Фев. 1, 2024
SUMMARY
Regulation
of
RNA
polymerase
II
(Pol
II)
transcription
is
closely
associated
with
cell
proliferation.
However,
it
remains
unclear
how
the
Pol
program
altered
in
cancer
to
favour
growth.
Here,
we
find
that
gene
expression
NELFCD
,
a
known
negative
elongation
factor,
up-regulated
colorectal
tumours.
To
dissect
direct
role
NELF-C
on
such
cancer,
employed
an
auxin-dependent
protein
degradation
system
for
combination
nascent
transcript
sequencing
technologies.
Strikingly,
demonstrated
acute
loss
globally
perturbs
termination
and
also
increases
rate,
independently
promoter-proximal
pausing.
This
results
into
DNA
replication
initiation
zones,
may
link
failure
cycle
transition
S
phase.
We
anticipate
NELF
will
be
potential
therapeutic
target
restrict
cancers
by
promoting
transcription-replication
conflict.
HIGHLIGHTS
Expression
tumors
mandatory
between
G1-S
phases
during
impairs
pausing
leads
invade
zones
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 6, 2024
Abstract
Regulation
of
RNA
polymerase
II
(Pol
II)
transcription
is
closely
associated
with
cell
proliferation.
However,
it
remains
unclear
how
the
Pol
program
altered
in
cancer
to
favour
growth.
Here,
we
find
that
gene
expression
NELFCD,
a
known
negative
elongation
factor,
up-regulated
colorectal
tumours.
To
dissect
direct
role
NELF-C
on
such
cancer,
employed
an
auxin-dependent
protein
degradation
system
for
combination
nascent
transcript
sequencing
technologies.
Strikingly,
demonstrated
acute
loss
globally
perturbs
termination
and
also
increases
rate,
independently
promoter-proximal
pausing.
This
results
into
DNA
replication
initiation
zones,
may
link
failure
cycle
transition
S
phase.
We
anticipate
NELF
will
be
potential
therapeutic
target
restrict
cancers
by
promoting
transcription-replication
conflict.
The EMBO Journal,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 25, 2024
Abstract
Lamina-associated
domains
(LADs)
are
large
chromatin
regions
that
associated
with
the
nuclear
lamina
(NL)
and
form
a
repressive
environment
for
transcription.
The
molecular
players
mediate
gene
repression
in
LADs
currently
unknown.
Here,
we
performed
FACS-based
whole-genome
genetic
screens
human
cells
using
LAD-integrated
fluorescent
reporters
to
identify
such
regulators.
Surprisingly,
screen
identified
very
few
NL
proteins,
but
revealed
roles
dozens
of
known
Among
these
negative
elongation
factor
(NELF)
complex
interacting
factors
involved
RNA
polymerase
pausing,
suggesting
regulation
transcription
is
mechanism
repress
LADs.
Furthermore,
remodeler
BAF
activation
Mediator
can
work
both
as
activators
repressors
LADs,
depending
on
local
context
possibly
by
rewiring
heterochromatin.
Our
data
indicate
fundamental
regulators
remodeling,
rather
than
interaction
play
major
role
within
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 5, 2024
Summary
Immediately
after
fertilization
the
genome
is
transcriptionally
quiescent.
Maternally
encoded
pioneer
transcription
factors
reprogram
chromatin
state
and
facilitate
of
zygotic
genome.
In
Drosophila
,
initiated
by
factor
Zelda.
While
Zelda-occupied
sites
are
enriched
with
histone
acetylation,
a
post-translational
mark
associated
active
cis
-regulatory
regions,
functional
relationship
between
Zelda
acetylation
in
activation
remained
unclear.
We
show
that
Zelda-mediated
recruitment
acetyltransferase
CBP
essential
for
transcription.
catalytic
activity
necessary
release
RNA
Polymerase
II
(Pol
II)
into
elongation
embryonic
development.
However,
also
activates
independent
through
Pol
recruitment.
Neither
nor
required
pioneering
function
Our
data
suggest
factor-mediated
conserved
mechanism
to
activate
but
this
role
separable
from
restructuring
accessibility.
Here,
we
investigated
the
potential
interaction
between
bromodomain-containing
protein
4
(BRD4),
an
established
epigenetic
modulator
and
transcriptional
coactivator,
p63,
a
member
of
p53
transcription
factor
family,
essential
for
epithelial
development
skin
homeostasis.
Our
protein–protein
assays
demonstrated
strong
conserved
physical
BRD4
family
members—p63,
p73,
p53—suggesting
shared
binding
region
among
these
proteins.
While
role
in
cancer
through
its
with
has
been
explored,
effects
Bromodomain
Extra
Terminal
(BET)
inhibitors
non-transformed
cells,
such
as
keratinocytes,
remain
largely
unknown.
functional
analyses
revealed
changes
cellular
proliferation
differentiation
keratinocytes
depleted
either
p63
or
BRD4,
which
were
further
supported
by
using
inhibitor
JQ1.
Transcriptomic
analyses,
chromatin
immunoprecipitation,
RT-qPCR
indicated
synergistic
mechanism
regulating
keratinocyte-specific
target
genes,
including
HK2,
FOXM1,
EVPL.
This
study
not
only
highlights
complex
relationship
members
but
also
suggests
maintaining
keratinocyte
functions.
findings
pave
way
exploration
therapeutic
applications
treating
disorders.
