Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Фев. 23, 2024
Abstract
Protein
translation
is
a
tightly
regulated
cellular
process
that
essential
for
gene
expression
and
protein
synthesis.
The
deregulation
of
this
increasingly
recognized
as
critical
factor
in
the
pathogenesis
various
human
diseases.
In
review,
we
discuss
how
deregulated
can
lead
to
aberrant
synthesis,
altered
functions,
disease
progression.
We
explore
key
mechanisms
contributing
translation,
including
functional
alterations
factors,
tRNA,
mRNA,
ribosome
function.
Deregulated
leads
abnormal
expression,
disrupted
signaling,
perturbed
functions-
all
which
contribute
pathogenesis.
development
profiling
techniques
along
with
mass
spectrometry-based
proteomics,
mRNA
sequencing
single-cell
approaches
have
opened
new
avenues
detecting
diseases
related
errors.
Importantly,
highlight
recent
advances
therapies
targeting
translation-related
disorders
their
potential
applications
neurodegenerative
diseases,
cancer,
infectious
cardiovascular
Moreover,
growing
interest
lies
targeted
aimed
at
restoring
precise
control
over
diseased
cells
discussed.
conclusion,
comprehensive
review
underscores
role
its
therapeutic
target.
Advancements
understanding
molecular
deregulation,
coupled
therapies,
offer
promising
improving
outcomes
Additionally,
it
will
unlock
doors
possibility
precision
medicine
by
offering
personalized
deeper
underpinnings
future.
Cell,
Год журнала:
2022,
Номер
185(23), С. 4428 - 4447.e28
Опубликована: Окт. 31, 2022
Human
brain
development
is
underpinned
by
cellular
and
molecular
reconfigurations
continuing
into
the
third
decade
of
life.
To
reveal
cell
dynamics
orchestrating
neural
maturation,
we
profiled
human
prefrontal
cortex
gene
expression
chromatin
accessibility
at
single-cell
resolution
from
gestation
to
adulthood.
Integrative
analyses
define
dynamic
trajectories
each
type,
revealing
major
reconfiguration
prenatal-to-postnatal
transition
in
all
types
followed
continuous
adulthood
identifying
regulatory
networks
guiding
developmental
programs,
states,
functions.
We
uncover
links
between
milestones,
characterize
diverse
timing
when
cells
acquire
adult-like
identify
convergence
distinct
origins.
further
their
regulators
implicated
neurological
disorders.
Finally,
using
this
reference,
benchmark
identities
maturation
states
organoid
models.
Together,
captures
landscape
cortical
development.
Nature,
Год журнала:
2023,
Номер
621(7978), С. 373 - 380
Опубликована: Сен. 13, 2023
Abstract
The
development
of
the
human
brain
involves
unique
processes
(not
observed
in
many
other
species)
that
can
contribute
to
neurodevelopmental
disorders
1–4
.
Cerebral
organoids
enable
study
a
context.
We
have
developed
CRISPR–human
organoids–single-cell
RNA
sequencing
(CHOOSE)
system,
which
uses
verified
pairs
guide
RNAs,
inducible
CRISPR–Cas9-based
genetic
disruption
and
single-cell
transcriptomics
for
pooled
loss-of-function
screening
mosaic
organoids.
Here
we
show
perturbation
36
high-risk
autism
spectrum
disorder
genes
related
transcriptional
regulation
uncovers
their
effects
on
cell
fate
determination.
find
dorsal
intermediate
progenitors,
ventral
progenitors
upper-layer
excitatory
neurons
are
among
most
vulnerable
types.
construct
developmental
gene
regulatory
network
cerebral
from
transcriptomes
chromatin
modalities
identify
disorder-associated
perturbation-enriched
modules.
Perturbing
members
BRG1/BRM-associated
factor
(BAF)
remodelling
complex
leads
enrichment
telencephalon
progenitors.
Specifically,
mutating
BAF
subunit
ARID1B
affects
transition
oligodendrocyte
interneuron
precursor
cells,
phenotype
confirmed
patient-specific
induced
pluripotent
stem
cell-derived
Our
paves
way
high-throughput
phenotypic
characterization
disease
susceptibility
organoid
models
with
state,
molecular
pathway
readouts.
Nature Biotechnology,
Год журнала:
2023,
Номер
41(12), С. 1746 - 1757
Опубликована: Март 27, 2023
Abstract
Metacells
are
cell
groupings
derived
from
single-cell
sequencing
data
that
represent
highly
granular,
distinct
states.
Here
we
present
aggregation
of
states
(SEACells),
an
algorithm
for
identifying
metacells
overcome
the
sparsity
while
retaining
heterogeneity
obscured
by
traditional
clustering.
SEACells
outperforms
existing
algorithms
in
comprehensive,
compact
and
well-separated
both
RNA
assay
transposase-accessible
chromatin
(ATAC)
modalities
across
datasets
with
discrete
types
continuous
trajectories.
We
demonstrate
use
to
improve
gene–peak
associations,
compute
ATAC
gene
scores
infer
activities
critical
regulators
during
differentiation.
Metacell-level
analysis
scales
large
is
particularly
well
suited
patient
cohorts,
where
per-patient
provides
more
robust
units
integration.
our
reveal
expression
dynamics
gradual
reconfiguration
landscape
hematopoietic
differentiation
uniquely
identify
CD4
T
activation
associated
disease
onset
severity
a
Coronavirus
Disease
2019
(COVID-19)
cohort.
Nature Genetics,
Год журнала:
2022,
Номер
54(12), С. 1881 - 1894
Опубликована: Дек. 1, 2022
Abstract
Histone
3
lysine27-to-methionine
(H3-K27M)
mutations
most
frequently
occur
in
diffuse
midline
gliomas
(DMGs)
of
the
childhood
pons
but
are
also
increasingly
recognized
adults.
Their
potential
heterogeneity
at
different
ages
and
locations
is
vastly
understudied.
Here,
through
dissecting
single-cell
transcriptomic,
epigenomic
spatial
architectures
a
comprehensive
cohort
patient
H3-K27M
DMGs,
we
delineate
how
age
anatomical
location
shape
glioma
cell-intrinsic
-extrinsic
features
light
shared
driver
mutation.
We
show
that
stem-like
oligodendroglial
precursor-like
cells,
present
across
all
clinico-anatomical
groups,
display
varying
levels
maturation
dependent
on
location.
reveal
previously
underappreciated
relationship
between
mesenchymal
cancer
cell
states
age,
linked
to
age-dependent
differences
immune
microenvironment.
Further,
resolve
organization
DMG
populations
identify
mitotic
oligodendroglial-lineage
niche.
Collectively,
our
study
provides
powerful
framework
for
rational
modeling
therapeutic
interventions.
We
analyzed
>700,000
single-nucleus
RNA
sequencing
profiles
from
106
donors
during
prenatal
and
postnatal
developmental
stages
identified
lineage-specific
programs
that
underlie
the
development
of
specific
subtypes
excitatory
cortical
neurons,
interneurons,
glial
cell
types,
brain
vasculature.
By
leveraging
chromatin
accessibility
data,
we
delineated
enhancer
gene
regulatory
networks
transcription
factors
control
commitment
lineages.
intersecting
our
results
with
genetic
risk
for
human
diseases,
types
lineages
most
vulnerable
to
insults
different
disorders,
especially
autism.
find
expression
up-regulated
in
female
cells
are
enriched
Our
study
captures
molecular
progression
across
development.
Nature,
Год журнала:
2023,
Номер
622(7982), С. 359 - 366
Опубликована: Сен. 27, 2023
Abstract
The
assembly
of
cortical
circuits
involves
the
generation
and
migration
interneurons
from
ventral
to
dorsal
forebrain
1–3
,
which
has
been
challenging
study
at
inaccessible
stages
late
gestation
early
postnatal
human
development
4
.
Autism
spectrum
disorder
other
neurodevelopmental
disorders
(NDDs)
have
associated
with
abnormal
interneuron
5
but
these
NDD
genes
affect
migration,
how
they
mediate
effects
remains
unknown.
We
previously
developed
a
platform
in
subpallial
organoids
assembloids
6
Here
we
integrate
CRISPR
screening
investigate
involvement
425
development.
first
screen
aimed
revealed
13
candidate
genes,
including
CSDE1
SMAD4
subsequently
conducted
an
more
than
1,000
that
identified
33
cytoskeleton-related
endoplasmic
reticulum-related
gene
LNPK
discovered
that,
during
reticulum
is
displaced
along
leading
neuronal
branch
before
nuclear
translocation.
deletion
interfered
this
displacement
resulted
migration.
These
results
highlight
power
CRISPR-assembloid
systematically
map
onto
reveal
disease
mechanisms.
Cell,
Год журнала:
2023,
Номер
186(6), С. 1179 - 1194.e15
Опубликована: Март 1, 2023
The
human
brain
undergoes
rapid
development
at
mid-gestation
from
a
pool
of
neural
stem
and
progenitor
cells
(NSPCs)
that
give
rise
to
the
neurons,
oligodendrocytes,
astrocytes
mature
brain.
Functional
study
these
cell
types
has
been
hampered
by
lack
precise
purification
methods.
We
describe
method
for
prospectively
isolating
ten
distinct
NSPC
developing
using
cell-surface
markers.
CD24−THY1−/lo
were
enriched
radial
glia,
which
robustly
engrafted
differentiated
into
all
three
lineages
in
mouse
THY1hi
marked
unipotent
oligodendrocyte
precursors
committed
an
oligodendroglial
fate,
CD24+THY1−/lo
excitatory
inhibitory
neuronal
lineages.
Notably,
we
identify
functionally
characterize
transcriptomically
THY1hiEGFRhiPDGFRA−
bipotent
glial
(GPC),
is
lineage-restricted
but
not
neurons.
Our
provides
framework
functional
neurodevelopment.
The
cellular
complexity
of
the
human
brain
is
established
via
dynamic
changes
in
gene
expression
throughout
development
that
mediated,
part,
by
spatiotemporal
activity
cis-regulatory
elements
(CREs).
We
simultaneously
profiled
and
chromatin
accessibility
45,549
cortical
nuclei
across
six
broad
developmental
time
points
from
fetus
to
adult.
identified
cell
type-specific
domains
which
highly
correlated
with
expression.
Differentiation
pseudotime
trajectory
analysis
indicates
at
CREs
precedes
transcription
structure
play
a
critical
role
neuronal
lineage
commitment.
In
addition,
we
mapped
temporally
specific
genetic
loci
implicated
neuropsychiatric
traits,
including
schizophrenia
bipolar
disorder.
Together,
our
results
describe
complex
regulation
composition
stages
determination
shed
light
on
impact
alterations
disease.