bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 27, 2024
Abstract
SLC35A2
encodes
a
UDP-galactose
transporter
essential
for
glycosylation
of
proteins
and
galactosylation
lipids
glycosaminoglycans.
Germline
genetic
variants
have
been
identified
in
congenital
disorders
somatic
linked
to
intractable
epilepsy
associated
with
malformations
cortical
development.
However,
the
functional
consequences
these
pathogenic
on
brain
development
network
integrity
remain
elusive.
In
this
study,
we
use
an
isogenic
human
induced
pluripotent
stem
cell-derived
neuron
model
comprehensively
interrogate
impact
loss
function
through
integration
cellular
molecular
biology,
protein
analysis,
neural
dynamics,
single
cell
electrophysiology.
We
show
that
result
disrupted
glycomic
signatures
precocious
neurodevelopment,
yielding
hypoactive,
asynchronous
networks.
This
aberrant
activity
is
attributed
inhibitory/excitatory
imbalance
as
characterization
composition
revealed
preferential
differentiation
towards
GABAergic
fate.
Additionally,
electrophysiological
recordings
synaptic
reveal
shift
excitatory/inhibitory
balance
increased
inhibitory
drive,
indicating
changes
occurring
specifically
at
pre-synaptic
terminal.
Our
study
first
provide
mechanistic
insight
regarding
early
connectivity
variant
harboring
neurons,
providing
important
groundwork
future
exploration
potential
therapeutic
interventions.
Current Opinion in Neurobiology,
Год журнала:
2025,
Номер
92, С. 103033 - 103033
Опубликована: Май 6, 2025
The
human
brain
has
undergone
remarkable
structural
and
functional
specializations
compared
to
that
of
nonhuman
primates
(NHPs),
underlying
the
advanced
cognitive
abilities
unique
humans.
However,
cellular
genetic
basis
driving
these
remains
largely
unknown.
Comparing
humans
our
closest
living
relatives,
chimpanzee
other
great
apes,
is
essential
for
identifying
truly
human-specific
features.
Recent
comparative
studies
with
closely
related
NHPs
at
single-cell
resolution
using
multimodal
genomic
profiling,
assisted
high-throughput
screening
have
provided
unprecedented
insights
into
features
their
underpinnings.
In
this
review,
we
synthesize
current
knowledge
evolution
molecular
levels,
emphasizing
how
changes
shaped
adaptations.
We
also
discuss
emerging
opportunities
presented
by
new
technologies
comprehensive
atlases
advancing
understanding
evolution.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Май 14, 2025
Comparative
anatomical
studies
of
primates
and
extinct
hominins,
including
Neanderthals,
show
that
the
modern
human
brain
is
characterised
by
a
disproportionately
enlarged
neocortex
relative
to
striatum.
To
explore
molecular
basis
this
difference,
we
screened
for
missense
mutations
are
unique
humans
occur
at
high
frequency
alter
post-translational
sites.
One
such
mutation
was
identified
in
DCHS1
,
protocadherin
family
gene,
it
found
disrupt
an
N-glycosylation
site
humans.
Using
CRISPR/Cas9-editing
introduced
into
human-induced
pluripotent
stem
cells
(hiPSCs)
ancestral
variant
present
Neanderthals
other
primates,
representing
state
before
human-specific
substitution.
Leveraging
hiPSCs-derived
neural
organoids,
observed
expansion
striatal
progenitors
expense
neocortex,
mirroring
distribution
seen
non-human
primates.
We
further
identify
ephrin
receptor
EPHA4
as
binding
partner
alterations
modulate
EPHA4-ephrin
signalling,
contributing
gradual
shift
neocortex-to-striatum
ratio
-
hallmark
organisation
our
species.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 17, 2024
Summary
Genome
organization
is
intricately
tied
to
regulating
genes
and
associated
cell
fate
decisions.
Here,
we
examine
the
positioning
functional
significance
of
human
genes,
grouped
by
their
lineage
restriction
level,
within
3D
genome.
We
reveal
that
different
levels
have
distinct
relationships
with
both
domains
loop
anchors,
remarkably
consistent
boundaries
across
types.
While
associations
each
group
are
primarily
type-specific,
conserved
maintain
greater
stability
genomic
features
disease
than
recently
evolved
genes.
Furthermore,
expression
these
various
tissues
follows
an
evolutionary
progression,
such
RNA
increase
from
young
restricted
ancient
present
in
most
species.
Thus,
gene
age,
function,
contribute
tissue-specific
regulation
development
disease.
Neural Regeneration Research,
Год журнала:
2023,
Номер
19(3), С. 489 - 490
Опубликована: Июль 20, 2023
Center
for
Cognition
and
Sociality,
Institute
Basic
Science
(IBS),
Daejeon,
South
Korea
(Lee
B)
Asia-Pacific
Glycomics
Reference
Site,
(An
HJ)
Graduate
School
of
Analytical
&
Technology,
Chungnam
National
University,
Correspondence
to:
Hyun
Joo
An,
PhD,
[email
protected].
Received
April
5,
2023
in
revised
form
28,
Accepted
May
15,
This
is
an
open-access
article
distributed
under
the
terms
Creative
Commons
Attribution-Noncommercial-Share
Alike
4.0
Unported,
which
permits
unrestricted
use,
distribution,
reproduction
any
medium,
provided
original
work
properly
cited.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 17, 2024
Abstract
The
protein
glycome
of
individual
cell
types
in
the
brain
is
unexplored,
despite
critical
function
these
modifications
development
and
disease.
In
aggregate,
most
abundant
asparagine
(N-)
linked
glycans
adult
are
high
mannose
structures,
specifically
Man
5
GlcNAc
2
(Man-5),
which
normally
exits
ER
for
further
processing
Golgi.
Mannose
structures
uncommon
other
organs
often
overlooked
or
excluded
studies.
To
understand
cell-specific
contributions
to
unique
N-glycome
its
abundance
Man-5,
we
performed
RNAseq
MALDI-MS
TOF
N-glycomics
at
several
timepoints
during
differentiation
multiple
types.
this
end,
homogeneous
cultures
glutamatergic
neurons,
GABAergic
brain-specific
endothelial
cells
were
generated
from
monoclonal
human
inducible
pluripotent
stem
(hiPSCs)
through
cellular
reprogramming.
Small
molecule
induction
stably
integrated
synthetic
transcription
units
driving
morphogen
expression
differentiated
with
distinct
patterns
mirroring
intact
tissue.
Comparing
uninduced
hiPSCs
each
type
revealed
identical
transcriptomic
glycomic
profiles
before
differentiation,
low
quantities
Man-5.
N-glycans
became
Man-5
immediate
precursor
Man-6,
presence
transcripts
encoding
enzymes
their
subsequent
modification.
Differentiation
showed
an
opposite
effect,
displaying
complex
terminal
late
secretory
pathway.
These
results
confirm
that
restricted
profile
programmed
into
neuronal
regulation
independent
transcriptome
under
tight
evolutionary
constraint.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 13, 2024
ABSTRACT
Background
Epigenetic
regulator
genes
play
critical
roles
in
controlling
cell
identity
and
are
frequently
disrupted
breast
cancers,
suggesting
a
key
driver
role
this
disease
its
associated
phenotypes.
However,
specific
epigenetic
drivers
(epidrivers)
of
mammary
plasticity
their
mechanistic
contributions
to
phenotype
poorly
characterized.
Methods
To
identify
potential
epidrivers
the
emergence
mesenchymal
cancer
stem
cell-like
phenotypes
non-tumorigenic
cells,
we
employed
CRISPR/Cas9
loss-of-function
screening
strategy
targeting
genes.
This
approach
was
followed
by
an
in-depth
validation
characterization
epigenomic,
transcriptomic,
proteomic
phenotypic
changes
resulting
from
disruption
putative
epidriver
gene
BAP1
.
Results
Our
investigation
revealed
that
loss
histone
deubiquitinase
impacts
cellular
processes
with
such
as
epithelial-to-mesenchymal
transition
(EMT)
actin
cytoskeleton
organization.
In
addition,
unveiled
resulted
overall
less
permissive
chromatin
downregulated
expression,
impacting
programs
control
glycosylation
leading
decreased
glycan
abundance
complexity.
rescue
restored
expression
several
deregulated
catalytic
activity-dependent
manner,
BAP1-mediated
regulation
largely
dependent
on
activity.
Conclusions
Overall,
our
results
point
reveal
novel
glycosylation.
