Chromatin and aberrant enhancer activity in KMT2A rearranged acute lymphoblastic leukemia
Current Opinion in Genetics & Development,
Год журнала:
2024,
Номер
86, С. 102191 - 102191
Опубликована: Апрель 4, 2024
To
make
a
multicellular
organism,
genes
need
to
be
transcribed
at
the
right
developmental
stages
and
in
tissues.
DNA
sequences
termed
'enhancers'
are
crucial
achieve
this.
Despite
concerted
efforts,
exact
mechanisms
of
enhancer
activity
remain
elusive.
Mixed
lineage
leukemia
(MLL
or
KMT2A)
rearrangements
(MLLr),
commonly
observed
cases
acute
lymphoblastic
(ALL)
myeloid
leukemia,
produce
novel
in-frame
fusion
proteins.
Recent
work
has
shown
that
MLL-AF4
protein
drives
aberrant
key
oncogenes
ALL,
dependent
on
continued
presence
complex
components.
As
well
as
providing
some
general
insights
into
function,
these
observations
may
also
provide
an
explanation
for
transcriptional
heterogeneity
MLLr
patients.
Язык: Английский
The α-globin super-enhancer acts in an orientation-dependent manner
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 25, 2025
Abstract
Individual
enhancers
are
defined
as
short
genomic
regulatory
elements,
bound
by
transcription
factors,
and
able
to
activate
cell-specific
gene
expression
at
a
distance,
in
an
orientation-independent
manner.
Within
mammalian
genomes,
enhancer-like
elements
may
be
found
individually
or
within
clusters
referred
locus
control
regions
super-enhancers
(SEs).
While
these
behave
similarly
individual
with
respect
cell
specificity,
distribution
their
orientation-dependence
has
not
been
formally
tested.
Here,
using
the
α-globin
model,
we
show
that
while
enhancer
works
manner,
direction
of
activity
SE
changes
its
orientation.
When
is
inverted
normal
chromosomal
context,
targets,
genes,
severely
reduced
normally
silent
genes
lying
upstream
upregulated.
These
findings
add
our
understanding
enhancer-promoter
specificity
precisely
transcription.
Язык: Английский
The roles of enhancer, especially super-enhancer-driven genes in tumor metabolism and immunity
International Journal of Biological Macromolecules,
Год журнала:
2025,
Номер
unknown, С. 142414 - 142414
Опубликована: Март 1, 2025
Язык: Английский
Is Enhancer Function Driven by Protein–Protein Interactions? From Bacteria to Leukemia
BioEssays,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 8, 2025
ABSTRACT
The
precise
regulation
of
the
transcription
genes
is
essential
for
normal
development
and
maintenance
life.
Aberrant
gene
expression
changes
drive
many
human
diseases.
Despite
this,
we
still
do
not
completely
understand
how
controlled
in
living
systems.
Enhancers
are
key
regulatory
elements
that
enable
cells
to
specifically
activate
response
environmental
cues,
or
a
stage
tissue‐specific
manner.
Any
model
enhancer
activity
needs
answer
two
main
questions:
(1)
enhancers
able
identify
act
on
specific
(2)
influence
transcription.
To
address
these
points,
first
outline
some
basic
principles
can
be
established
from
simpler
prokaryotic
systems,
then
discuss
recent
work
aberrant
leukemia.
We
argue
highly
protein–protein
interactions
driver
enhancer‐promoter
proximity,
allowing
enhancer‐bound
factors
directly
RNA
polymerase
Язык: Английский
DNA G-quadruplex structures act as functional elements in α- and β-globin enhancers
Genome biology,
Год журнала:
2025,
Номер
26(1)
Опубликована: Июнь 4, 2025
Abstract
Background
Enhancer
elements
interact
with
target
genes
at
a
distance
to
modulate
their
expression,
but
the
molecular
details
of
enhancer–promoter
interaction
are
incompletely
understood.
G-quadruplex
DNA
secondary
structures
(G4s)
have
recently
been
shown
co-occur
3D
chromatin
interactions;
however,
functional
importance
G4s
within
enhancers
remains
unclear.
Results
In
this
study,
we
identify
novel
G4
two
locus
control
regions
human
α-
and
β-globin
loci.
We
find
that
mutating
motifs
by
genome
editing
prevents
folding
into
in
cells
disrupts
interactions
gene
expression
manner
comparable
whole
enhancer
deletion.
Furthermore,
restoration
structure
formation
using
dissimilar
G4-forming
primary
sequence
recovers
specific
enhancer-gene
expression.
Through
proteomic,
biophysical,
genomic
profiling,
tightly
linked
maintenance
an
active
state
RNA
polymerase
II
recruitment
regulate
Conclusions
Our
study
shows
folded
can
act
as
mediate
support
enhancer-driven
globin
regulation.
Язык: Английский
A mammalian tripartite enhancer cluster controls hypothalamic Pomc expression, food intake, and body weight
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(18)
Опубликована: Апрель 23, 2024
Food
intake
and
energy
balance
are
tightly
regulated
by
a
group
of
hypothalamic
arcuate
neurons
expressing
the
proopiomelanocortin
(
POMC)
gene.
In
mammals,
arcuate-specific
POMC
expression
is
driven
two
cis
-acting
transcriptional
enhancers
known
as
nPE1
nPE2.
Because
mutant
mice
lacking
these
still
showed
Pomc
mRNA,
we
searched
for
additional
elements
contributing
to
expression.
By
combining
molecular
evolution
with
reporter
gene
in
transgenic
zebrafish
mice,
here,
identified
mammalian
enhancer
that
named
nPE3,
carrying
several
binding
sites
also
present
nPE2
transcription
factors
activate
neuronal
expression,
such
ISL1,
NKX2.1,
ERα.
We
found
nPE3
originated
lineage
leading
placental
mammals
remained
under
purifying
selection
all
orders,
although
it
was
lost
Simiiformes
(monkeys,
apes,
humans)
following
unique
segmental
deletion
event.
Interestingly,
ablation
from
mouse
genome
led
drastic
reduction
(>70%)
mRNA
during
development
only
moderate
(<33%)
adult
mice.
Comparison
between
double
(nPE1
nPE2)
triple
(nPE1,
nPE2,
nPE3)
mutants
revealed
relative
contribution
its
importance
control
food
adiposity
male
female
Altogether,
results
demonstrate
integrates
tripartite
cluster
partially
redundant
upon
convergent
evolutionary
process
critical
body
weight
homeostasis.
Язык: Английский
Reporter CRISPR screens decipher cis- and trans-regulatory principles at the Xist locus
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 10, 2024
Abstract
Developmental
genes
are
controlled
by
an
ensemble
of
cis
-acting
regulatory
elements
(REs),
which
in
turn
respond
to
multiple
trans
transcription
factors
(TFs).
Understanding
how
a
-regulatory
landscape
integrates
information
from
many
dynamically
expressed
TFs
has
remained
challenge.
We
develop
combined
CRISPR-screening
approach
using
endogenous
RNA
and
RE-reporters
as
readouts.
Applied
the
Xist
locus,
crucial
for
X-chromosome
inactivation
females,
this
method
allows
us
comprehensively
identify
Xist-controlling
map
their
TF-RE
wiring.
find
group
transiently
that
regulate
proximal
REs,
driving
binary
activation
expression.
These
basal
activators
more
highly
cells
with
two
X
chromosomes,
potentially
female-specific
upregulation.
A
second
set
developmental
is
upregulated
later
during
differentiation
targets
distal
REs.
This
axis
achieve
high
levels
RNA,
necessary
inactivation.
Our
findings
support
model
gene
regulation
targeting
REs
drive
ON-OFF
decisions,
while
interacting
control
output.
Язык: Английский