The Journal of Experimental Medicine,
Год журнала:
2024,
Номер
222(1)
Опубликована: Дек. 9, 2024
The
cohesin
complex
is
a
critical
regulator
of
gene
expression.
STAG2
the
most
frequently
mutated
subunit
across
several
cancer
types
and
key
tumor
suppressor
in
lung
cancer.
Here,
we
coupled
somatic
CRISPR-Cas9
genome
editing
barcoding
with
an
autochthonous
oncogenic
KRAS-driven
model
showed
that
uniquely
tumor-suppressive
among
all
core
auxiliary
components.
heterodimeric
components
PAXIP1
PAGR1
have
highly
correlated
effects
human
cell
lines,
are
suppressors
vivo,
epistatic
to
tumorigenesis
vivo.
inactivation
elicits
changes
expression,
chromatin
accessibility,
3D
conformation
impact
state.
Gene
expression
accessibility
similarities
between
STAG2-
PAXIP1-deficient
neoplastic
cells
further
relate
STAG2-cohesin
PAXIP1/PAGR1.
These
findings
reveal
STAG2-PAXIP1/PAGR1
axis
uncover
novel
PAXIP1-dependent
PAXIP1-independent
STAG2-cohesin-mediated
mechanisms
suppression.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 8, 2024
Summary
Chromosome
organization
ensures
accurate
DNA
replication,
segregation,
gene
regulation
and
damage
repair.
Across
the
tree
of
life,
protein
assemblages
termed
Structural
Maintenance
Chromosomes
(SMC)
complexes
determine
chromosome
organization.
Eukaryotes
usually
have
four
SMC
complex
types
(condensin
I,
condensin
II,
cohesin,
SMC5/6),
whereas
prokaryotes
mostly
one.
The
expanded
set
is
probably
needed
to
accommodate
considerably
larger
eukaryotic
genomes.
Despite
their
essential
functions,
exhibit
notable
variation
among
model
organisms,
suggesting
underexplored
diversity
across
eukaryotes.
Here,
we
provide
a
thorough
reconstruction
evolution
subunits
accessory
proteins
We
show
that
last
common
ancestor
(LECA)
had
all
complete
complexes,
supporting
notion
LECA
was
already
sophisticated
cell.
At
later
timepoints,
II
lost
at
least
thirty
times,
rendering
it
one
most
frequently
cellular
machineries.
identify
multiple
components
(e.g.,
Sororin,
Securin,
Nse5,
Nse6)
as
much
more
ancient
widespread
than
previously
appreciated.
Finally,
traced
prokaryotic
origins
these
propose
an
duplicated
in
TACK
Asgard
archaea,
archaeal
inventory
further
through
duplications,
highlighting
importance
events
emergence
complexity.
Altogether,
our
results
address
questions
raise
new
ones
about
how
affected
genome
organizations
ancestral
contemporary
organisms.
SUMMARY
NIPBL
promotes
chromatin
loop
extrusion
by
the
cohesin
complex
until
it
stalls
at
convergently
oriented
CTCF
sites,
leading
to
formation
of
structural
loops.
However,
what
extent
contributes
establishment
vs
maintenance
cis
-regulatory
element
(CRE)
connectivity
is
poorly
understood.
Here,
we
explored
de
novo
folding
patterns
mitosis-to-G1-phase
transition
upon
acute
loss.
depletion
primarily
impaired
cohesin-mediated
loops
with
dependence
being
proportional
length.
In
contrast,
majority
CRE
were
established
independently
regardless
slowed
re-formation
weak
enhancers.
Transcription
genes
NIPBL-independent
anchors
was
activated
normally
in
absence
NIPBL.
sum,
most
regulatory
contacts
and
gene
transcription
following
mitotic
exit
independent
extrusion.
Nature Communications,
Год журнала:
2023,
Номер
14(1)
Опубликована: Окт. 9, 2023
Abstract
Transcription
reprogramming
during
cell
differentiation
involves
targeting
enhancers
to
genes
responsible
for
establishment
of
fates.
To
understand
the
contribution
CTCF-mediated
chromatin
organization
lineage
commitment,
we
analyzed
3D
architecture
human
embryonic
stem
cells
into
pancreatic
islet
organoids.
We
find
that
CTCF
loops
are
formed
and
disassembled
at
different
stages
process
by
either
recruitment
new
anchor
sites
or
use
pre-existing
not
previously
involved
in
loop
formation.
Recruitment
genome
demethylation
H3K9me3
H3K9me2,
DNA,
pioneer
factors,
positioning
nucleosomes
flanking
sites.
Existing
formation
become
functional
anchors
via
cohesin
loading
containing
NIPBL
YY1
between
anchors.
In
both
cases,
leads
strengthening
enhancer
promoter
interactions
increased
transcription
adjacent
These
results
suggest
an
important
role
controlling
gene
expression
differentiation.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(2), С. 1280 - 1280
Опубликована: Янв. 20, 2024
The
human
STAG2
protein
is
an
essential
component
of
the
cohesin
complex
involved
in
cellular
processes
gene
expression,
DNA
repair,
and
genomic
integrity.
Somatic
mutations
sequence
have
been
associated
with
various
types
cancer,
while
congenital
variants
linked
to
developmental
disorders
such
as
Mullegama–Klein–Martinez
syndrome,
X-linked
holoprosencephaly-13,
Cornelia
de
Lange
syndrome.
In
complex,
direct
interaction
NIPBL,
RAD21,
CTCF
proteins
has
described.
function
within
still
unknown,
but
it
related
its
binding
capacity
modulated
by
other
three
proteins.
Every
missense
variant
described
for
located
regions
one
these
interactions.
present
work,
we
model
structure
12
STAG2,
well
two
NIPBl
RAD21
at
zone,
then
analyze
their
behavior
through
molecular
dynamic
simulations,
comparing
them
same
simulation
wild-type
protein.
This
will
allow
effects
be
rationalized
atomic
level
provide
clues
how
functions
complex.
Epigenetics & Chromatin,
Год журнала:
2024,
Номер
17(1)
Опубликована: Апрель 20, 2024
Nuclear
organization
of
interphase
chromosomes
involves
individual
chromosome
territories,
"open"
and
"closed"
chromatin
compartments,
topologically
associated
domains
(TADs)
loops.
The
DNA-
RNA-binding
transcription
factor
CTCF
together
with
the
cohesin
complex
serve
as
major
organizers
architecture.
Cellular
differentiation
is
driven
by
temporally
spatially
coordinated
gene
expression
that
requires
changes
loci
various
complexities.
Lens
represents
an
advantageous
system
to
probe
transcriptional
mechanisms
underlying
tissue-specific
including
high
outputs
crystallin
genes
until
mature
lens
fiber
cells
degrade
their
nuclei.
Chromatin
between
mouse
embryonic
stem
(ES)
cells,
newborn
(P0.5)
epithelium
were
analyzed
using
Hi-C.
Localization
in
both
chromatins
was
determined
ChIP-seq
compared
ES
cells.
Quantitative
analyses
show
differences
number
size
TADs
loop
these
three
cell
types.
In
depth
similarities
samples
exemplified
overlaps
compartments
A
B.
epithelium-specific
peaks
are
found
mostly
methylated
genomic
regions
while
fiber-specific
shared
occur
within
unmethylated
DNA
regions.
Major
loops
illustrated
at
~
500
kb
Pax6
locus,
encoding
critical
regulatory
a
larger
15
Mb
WAGR
containing
other
linked
human
congenital
diseases.
Hi-C
data
(TADs
loops)
ATAC-seq,
CTCF,
H3K27ac,
H3K27me3
ENCODE
cis-regulatory
sites
shown
detail
for
Pax6,
Sox1
Hif1a
loci,
multiple
important
required
morphogenesis.
majority
marked
unexpectedly
CTCF-binding
across
transcribed
Our
study
has
generated
first
on
3-dimensional
(3D)
nuclear
fibers
directly
These
findings
generate
novel
insights
into
lens-specific
control,
open
new
research
avenues
condensates
enable
studies
non-coding
genetic
variants
cataract
ocular
abnormalities.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 3, 2024
The
CRL4-DCAF15
E3
ubiquitin
ligase
complex
is
targeted
by
the
aryl-sulfonamide
molecular
glues,
leading
to
neo-substrate
recruitment,
ubiquitination,
and
proteasomal
degradation.
However,
physiological
function
of
DCAF15
remains
unknown.
Using
a
domain-focused
genetic
screening
approach,
we
reveal
as
an
acute
myeloid
leukemia
(AML)-biased
dependency.
Loss
results
in
suppression
AML
through
compromised
replication
fork
integrity
consequent
accumulation
DNA
damage.
Accordingly,
loss
sensitizes
stress-inducing
therapeutics.
Mechanistically,
discover
that
directly
interacts
with
SMC1A
protein
cohesin
destabilizes
regulatory
factors
PDS5A
CDCA5.
CDCA5
removal
precludes
acetylation
on
chromatin,
resulting
uncontrolled
chromatin
loop
extrusion,
defective
replication,
apoptosis.
Collectively,
our
findings
uncover
endogenous,
cell
autonomous
sustaining
proliferation
post-translational
control
dynamics.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 20, 2025
The
three-dimensional
folding
of
chromosomes
is
essential
for
nuclear
functions
such
as
DNA
replication
and
gene
regulation.
emergence
chromatin
architecture
thus
an
important
process
during
embryogenesis.
To
shed
light
on
the
molecular
kinetic
underpinnings
formation,
we
characterized
biophysical
properties
cohesin
CTCF
binding
to
their
changes
upon
cofactor
depletion
using
single-molecule
imaging
in
live
developing
zebrafish
embryos.
We
found
that
chromatin-bound
fractions
both
increased
significantly
between
1000-cell
shield
stages,
which
could
explain
through
association
dissociation
rates.
Moreover,
increasing
restricted
motion,
potentially
via
loop
extrusion,
showed
distinct
stage-dependent
distribution.
Polymer
simulations
with
experimentally
derived
parameters
recapitulated
observed
gradual
architecture.
Our
findings
reveal
kinetics
underlying
formation
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Март 3, 2025
Abstract
Primary
constriction
of
the
M-phase
chromosome
serves
as
a
marker
for
kinetochore
position.
Underlying
this
observation
is
concept
that
spatially
linked
with
pericentromere
where
sister-chromatids
are
cohered.
Here,
we
find
an
unconventional
chromatid-cohesion
pattern
in
Peromyscus
oocytes,
sister
chromatids
cohered
at
end,
separated
from
kinetochore.
This
distal
locus
enriches
cohesin
protectors
specifically
during
meiosis,
and
chromosomes
additional
cohesion
site
exhibit
enhanced
protection
anaphase
I
compared
to
those
without
it,
implying
adaptive
evolution
ensure
meiosis.
The
corresponds
centromeric
satellite
block,
located
far
block
building
Analyses
on
three
species
reveal
internal
consistently
assembles
mitosis
whereas
selectively
meiosis
promote
cohesion.
Our
study
demonstrates
regulation
flexible,
controlling
segregation
cell-type
dependent
manner.
Diagnostics,
Год журнала:
2025,
Номер
15(9), С. 1076 - 1076
Опубликована: Апрель 24, 2025
Background:
Previously
reported
STAG1
gene-related
cohesinopathies
describe
a
range
of
clinical
features,
typically
including
intellectual
disability
(ID),
facial
dysmorphisms,
and
limb
anomalies.
Case
presentation:
We
present
the
case
an
8-year-old
girl
with
main
findings
ID,
central
precocious
puberty
(CPP),
bone
fragility.
Panel
genetic
testing
revealed
pathogenic
variant,
NM_005862.3:c.2116del
p.(Asp706Ilefs*15),
which
can
only
partially
explain
phenotype.
Reports
STAG1-related
cohesinopathies,
ours,
have
consistently
described
developmental
disabilities.
In
our
case,
etiology
CPP
fragility
remains
unexplained.
discuss
challenges
limitations
current
molecular
tools
in
assessing
cases
overlapping,
apparently
unlinked
phenotypes,
while
speculating
whether
common
occurrence
could
be
explained
by
instead.
Conclusions:
The
spectrum
is
still
poorly
understood.
Complex
phenotypes
unrelated
features
warrant
further
careful
investigation
illustrate
diagnosis.