Nature,
Journal Year:
2021,
Volume and Issue:
598(7879), P. 205 - 213
Published: Oct. 6, 2021
Abstract
During
mammalian
development,
differences
in
chromatin
state
coincide
with
cellular
differentiation
and
reflect
changes
the
gene
regulatory
landscape
1
.
In
developing
brain,
cell
fate
specification
topographic
identity
are
important
for
defining
2
confer
selective
vulnerabilities
to
neurodevelopmental
disorders
3
Here,
identify
cell-type-specific
accessibility
patterns
human
we
used
a
single-cell
assay
transposase
by
sequencing
(scATAC-seq)
primary
tissue
samples
from
forebrain.
We
applied
unbiased
analyses
genomic
loci
that
undergo
extensive
cell-type-
brain-region-specific
during
neurogenesis,
an
integrative
analysis
predict
candidate
elements.
found
cerebral
organoids
recapitulate
most
putative
enhancer
but
lack
many
open
regions
vivo.
Systematic
comparison
of
across
brain
revealed
unexpected
diversity
among
neural
progenitor
cells
cortex
implicated
retinoic
acid
signalling
neuronal
lineage
prefrontal
cortex.
Together,
our
results
reveal
contribution
emerging
type
provide
blueprint
evaluating
fidelity
robustness
as
model
cortical
development.
Science,
Journal Year:
2018,
Volume and Issue:
362(6420)
Published: Dec. 13, 2018
Most
genetic
risk
for
psychiatric
disease
lies
in
regulatory
regions,
implicating
pathogenic
dysregulation
of
gene
expression
and
splicing.
However,
comprehensive
assessments
transcriptomic
organization
diseased
brains
are
limited.
In
this
work,
we
integrated
genotypes
RNA
sequencing
brain
samples
from
1695
individuals
with
autism
spectrum
disorder
(ASD),
schizophrenia,
bipolar
disorder,
as
well
controls.
More
than
25%
the
transcriptome
exhibits
differential
splicing
or
expression,
isoform-level
changes
capturing
largest
effects
enrichments.
Coexpression
networks
isolate
disease-specific
neuronal
alterations,
microglial,
astrocyte,
interferon-response
modules
defining
previously
unidentified
neural-immune
mechanisms.
We
genomic
data
to
perform
a
transcriptome-wide
association
study,
prioritizing
loci
likely
mediated
by
cis
on
expression.
This
characterization
molecular
pathology
across
three
major
disorders
provides
resource
mechanistic
insight
therapeutic
development.
Science,
Journal Year:
2020,
Volume and Issue:
367(6484)
Published: March 19, 2020
The
cerebral
cortex
underlies
our
complex
cognitive
capabilities,
yet
little
is
known
about
the
specific
genetic
loci
that
influence
human
cortical
structure.
To
identify
variants
affect
structure,
we
conducted
a
genome-wide
association
meta-analysis
of
brain
magnetic
resonance
imaging
data
from
51,665
individuals.
We
analyzed
surface
area
and
average
thickness
whole
34
regions
with
functional
specializations.
identified
199
significant
found
enrichment
for
influencing
total
within
regulatory
elements
are
active
during
prenatal
development,
supporting
radial
unit
hypothesis.
Loci
regional
cluster
near
genes
in
Wnt
signaling
pathways,
which
progenitor
expansion
areal
identity.
Variation
structure
genetically
correlated
function,
Parkinson's
disease,
insomnia,
depression,
neuroticism,
attention
deficit
hyperactivity
disorder.
Science,
Journal Year:
2018,
Volume and Issue:
362(6420)
Published: Dec. 14, 2018
INTRODUCTION
The
brain
is
responsible
for
cognition,
behavior,
and
much
of
what
makes
us
uniquely
human.
development
the
a
highly
complex
process,
this
process
reliant
on
precise
regulation
molecular
cellular
events
grounded
in
spatiotemporal
transcriptome.
Disruption
can
lead
to
neuropsychiatric
disorders.
RATIONALE
regulatory,
epigenomic,
transcriptomic
features
human
have
not
been
comprehensively
compiled
across
time,
regions,
or
cell
types.
Understanding
etiology
disorders
requires
knowledge
just
endpoint
differences
between
healthy
diseased
brains
but
also
developmental
contexts
which
these
arise.
Moreover,
an
emerging
body
research
indicates
that
many
aspects
physiology
are
well
recapitulated
model
organisms,
therefore
it
necessary
be
understood
broader
context
developing
adult
brain.
RESULTS
Here
we
describe
generation
analysis
variety
genomic
data
modalities
at
tissue
single-cell
levels,
including
transcriptome,
DNA
methylation,
histone
modifications
multiple
regions
ranging
age
from
embryonic
through
adulthood.
We
observed
widespread
transition
beginning
during
late
fetal
consisting
sharply
decreased
regional
differences.
This
reduction
coincided
with
increases
transcriptional
signatures
mature
neurons
expression
genes
associated
dendrite
development,
synapse
neuronal
activity,
all
were
temporally
synchronous
neocortical
areas,
as
myelination
oligodendrocytes,
asynchronous.
MEF2C
,
SATB2
TCF4
genetic
associations
brain-related
traits
disorders,
converged
small
number
modules
exhibiting
spatial
specificity.
CONCLUSION
generated
applied
our
dataset
document
epigenetic
changes
then
related
those
major
These
allowed
identify
genes,
types,
gene
coexpression
modules,
loci
where
disease
risk
might
converge,
demonstrating
utility
providing
new
insights
into
disease.
Spatiotemporal
dynamics
risks.
Human
begins
continues
adulthood
(top).
Integrating
(bottom
left)
revealed
age-
type–specific
properties
global
patterns
dynamics,
middle).
variation
(brown,
high;
purple,
low)
regulatory
elements
brains,
signatures,
right;
gray
circles
indicate
enrichment
corresponding
among
module
genes).
Relationships
depicted
panel
do
correspond
specific
observations.
CBC,
cerebellar
cortex;
STR,
striatum;
HIP,
hippocampus;
MD,
mediodorsal
nucleus
thalamus;
AMY,
amygdala.
Science,
Journal Year:
2019,
Volume and Issue:
366(6469), P. 1134 - 1139
Published: Nov. 15, 2019
Noncoding
genetic
variation
is
a
major
driver
of
phenotypic
diversity,
but
functional
interpretation
challenging.
To
better
understand
common
associated
with
brain
diseases,
we
defined
noncoding
regulatory
regions
for
cell
types
the
human
brain.
Whereas
psychiatric
disorders
were
primarily
variants
in
transcriptional
enhancers
and
promoters
neurons,
sporadic
Alzheimer's
disease
(AD)
largely
confined
to
microglia
enhancers.
Interactome
maps
connecting
disease-risk
cell-type-specific
revealed
an
extended
gene
network
AD.
Deletion
microglia-specific
enhancer
harboring
AD-risk
ablated
BIN1
expression
microglia,
not
neurons
or
astrocytes.
These
findings
revise
expand
list
genes
likely
be
influenced
by
AD
suggest
probable
which
they
function.
