Cancer Discovery,
Год журнала:
2022,
Номер
13(3), С. 746 - 765
Опубликована: Дек. 1, 2022
The
dysregulation
of
developmental
and
stem
cell-associated
genes
is
a
common
phenomenon
during
cancer
development.
Around
half
patients
with
acute
myeloid
leukemia
(AML)
express
high
levels
HOXA
cluster
MEIS1.
Most
these
AML
cases
harbor
an
NPM1
mutation
(NPM1c),
which
encodes
for
oncoprotein
mislocalized
from
the
nucleolus
to
cytoplasm.
How
NPM1c
expression
in
hematopoietic
cells
leads
its
characteristic
gene-expression
pattern
remains
unclear.
Here,
we
show
that
directly
binds
specific
chromatin
targets,
are
co-occupied
by
histone
methyltransferase
KMT2A
(MLL1).
Targeted
degradation
rapid
decrease
gene
loss
RNA
polymerase
II,
as
well
activating
modifications
at
targets.
We
demonstrate
regulates
oncogenic
collaboration
MLL1
complex
define
mechanism
MLL1-Menin
small-molecule
inhibitors
produce
clinical
responses
NPM1-mutated
AML.
uncovered
important
functional
role
mutant
crucial
direct
driver
can
bind
cooperate
MLL
complex,
providing
first
insight
into
Menin-MLL
inhibition
leukemias.
See
related
article
Wang
et
al.,
p.
724.
This
highlighted
In
Issue
feature,
517.
Science,
Год журнала:
2020,
Номер
368(6489), С. 387 - 394
Опубликована: Март 19, 2020
Bromodomain
inhibitors
revisited
and
extraterminal
domain
(BET)
proteins
contribute
to
the
pathogenesis
of
cancer
immune
diseases
through
their
effects
on
transcriptional
regulation.
BET
contain
two
nearly
identical
bromodomains,
BD1
BD2,
structural
modules
that
have
attracted
great
interest
as
targets
for
drug
development.
First-generation
drugs
inhibited
both
BD2
showed
promising
therapeutic
activity
in
preclinical
models
but
proved
be
less
efficacious
clinical
trials.
Gilan
et
al.
took
a
different
approach
designed
selectively
or
(see
Perspective
by
Filippakopoulos
Knapp).
They
found
altered
gene
expression
ways
had
greater
than
inflammation
autoimmune
disease.
Science
,
this
issue
p.
387
;
see
also
367
Abstract
We
developed
Lisa
(
http://lisa.cistrome.org/
)
to
predict
the
transcriptional
regulators
(TRs)
of
differentially
expressed
or
co-expressed
gene
sets.
Based
on
input
sets,
first
uses
histone
mark
ChIP-seq
and
chromatin
accessibility
profiles
construct
a
model
related
regulation
these
genes.
Using
TR
peaks
imputed
binding
sites,
probes
models
using
in
silico
deletion
find
most
relevant
TRs.
Applied
sets
derived
from
targeted
TF
perturbation
experiments,
boosted
performance
cistromes
outperformed
alternative
methods
identifying
perturbed
Genome Research,
Год журнала:
2021,
Номер
31(7), С. 1290 - 1295
Опубликована: Июнь 8, 2021
Sequencing
technologies
using
nucleotide
conversion
techniques
such
as
cytosine
to
thymine
in
bisulfite-seq
and
SLAM
seq
are
powerful
tools
explore
the
chemical
intricacies
of
cellular
processes.
To
date,
no
one
has
developed
a
unified
methodology
for
aligning
converted
sequences
consolidating
alignment
these
package.
In
this
paper,
we
describe
hierarchical
indexing
spliced
transcripts-3
nucleotides
(HISAT-3N),
which
can
rapidly
accurately
align
consisting
any
by
leveraging
index
repeat
algorithms
originally
HISAT
software.
Tests
on
real
simulated
data
sets
show
that
HISAT-3N
is
faster
than
other
modern
systems,
with
greater
accuracy,
higher
scalability,
smaller
memory
requirements.
therefore
becomes
an
ideal
aligner
when
used
sequence
technologies.
Nature,
Год журнала:
2023,
Номер
615(7951), С. 339 - 348
Опубликована: Март 1, 2023
Abstract
Trimethylation
of
histone
H3
lysine
4
(H3K4me3)
is
associated
with
transcriptional
start
sites
and
has
been
proposed
to
regulate
transcription
initiation
1,2
.
However,
redundant
functions
the
H3K4
SET1/COMPASS
methyltransferase
complexes
complicate
elucidation
specific
role
H3K4me3
in
regulation
3,4
Here,
using
mouse
embryonic
stem
cells
as
a
model
system,
we
show
that
acute
ablation
shared
subunits
leads
complete
loss
all
methylation.
Turnover
occurs
more
rapidly
than
H3K4me1
H3K4me2
dependent
on
KDM5
demethylases.
Notably,
does
not
have
detectable
effects
but
widespread
decrease
output,
an
increase
RNA
polymerase
II
(RNAPII)
pausing
slower
elongation.
We
required
for
recruitment
integrator
complex
subunit
11
(INTS11),
which
essential
eviction
paused
RNAPII
Thus,
our
study
demonstrates
distinct
pause-release
elongation
rather
initiation.
