Mutating
replication-dependent
(RD)
histone
genes
is
an
important
tool
for
understanding
chromatin-based
epigenetic
regulation.
Deploying
this
in
metazoans
particularly
challenging
because
RD
histones
these
organisms
are
typically
encoded
by
many
genes,
often
located
at
multiple
loci.
Such
gene
arrangements
make
the
ability
to
generate
homogenous
mutant
genotypes
site-specific
editing
quite
difficult.
Drosophila
melanogaster
provides
a
solution
problem
organized
into
single
large
tandem
array
that
can
be
deleted
and
replaced
with
transgenes
containing
genes.
In
last
∼15
years
several
different
replacement
platforms
were
developed
using
simple
strategy.
However,
each
platform
contains
weaknesses
preclude
full
use
of
powerful
developmental
genetic
capabilities
available
researchers.
Here
we
describe
development
newly
engineered
rectifies
weaknesses.
We
used
CRISPR
precisely
delete
(HisC),
replacing
it
multifunctional
cassette
permits
insertion
either
one
or
two
synthetic
arrays
selectable
markers.
designed
selectively
integrated
specific
tissues
recombinases.
also
present
method
rapidly
synthesizing
any
genotype
Golden
Gate
cloning
technologies.
These
improvements
facilitate
generation
cells
various
stages
provide
opportunity
apply
forward
strategies
interrogate
chromatin
structure
Journal of Clinical Investigation,
Год журнала:
2024,
Номер
134(20)
Опубликована: Окт. 14, 2024
As
epigenetic
therapies
continue
to
gain
ground
as
potential
treatment
strategies
for
cancer
and
other
diseases,
compounds
that
target
histone
lysine
methylation
the
enzyme
complexes
represent
a
major
frontier
therapeutic
development.
Clinically
viable
targeting
activities
of
methyltransferases
(HKMT)
demethylases
(HKDMs)
have
only
recently
begun
emerge
following
FDA
approval
EZH2
inhibitor
tazemetostat
in
2020
remain
limited
well-studied
SET
domain-containing
HKMTs
their
opposing
HKDMs.
These
include
H3K27
EZH2/EZH1,
singular
H3K79
methyltransferase
DOT1L,
H3K4
MLL1/COMPASS
well
H3K9
H3K36
methyltransferases.
They
additionally
H3K4/9-preferential
demethylase
LSD1
H3K4-,
H3K27-,
H3K36-preferential
KDM5,
KDM6,
KDM2
subfamilies,
respectively.
This
Review
discusses
results
recent
clinical
preclinical
studies
relevant
all
these
existing
therapies.
It
provides
an
update
on
advancements
development,
more
basic
molecular
understanding,
within
past
5
years
approximately.
also
offers
perspective
departs
from
long-predominant
"histone
code"
metaphor,
emphasizing
complex-disrupting
inhibitors
proximity-based
approaches
rather
than
catalytic
domain
outlook
future
Journal of Physiology and Biochemistry,
Год журнала:
2023,
Номер
79(4), С. 901 - 924
Опубликована: Авг. 25, 2023
Non-alcoholic
fatty
liver
disease
(NAFLD)
is
a
multifactorial
condition
with
complex
etiology.
Its
incidence
increasing
globally
in
parallel
the
obesity
epidemic,
and
it
now
considered
most
common
Western
countries.
The
precise
mechanisms
underlying
development
progression
of
NAFLD
are
still
poorly
understood.
dysregulation
epigenetic
epitranscriptomic
increasingly
recognized
to
play
pathogenic
roles
multiple
conditions,
including
chronic
diseases.
Here,
we
have
performed
comprehensive
analysis
expression
genes
total
903
tissue
samples
corresponding
patients
normal
liver,
obese
patients,
non-alcoholic
(NAFL)
steatohepatitis
(NASH),
advancing
stages
progression.
We
integrated
ten
transcriptomic
datasets
an
unbiased
manner,
enabling
their
robust
comparison.
describe
complete
landscape
genes'
along
course
disease.
identify
signatures
significantly
dysregulated
association
progression,
particularly
fibrosis
development.
Most
these
effectors
not
been
previously
described
human
NAFLD,
altered
may
implications.
also
enzymes
involved
metabolism
substrates
cofactors
effectors.
This
study
provides
novel
information
on
pathogenesis
guide
identification
drug
targets
treat
this
its
towards
hepatocellular
carcinoma.
Differentiation,
Год журнала:
2024,
Номер
136, С. 100746 - 100746
Опубликована: Янв. 14, 2024
Epigenetic
regulation
is
a
critical
component
of
lineage
determination.
Adipogenesis
the
process
through
which
uncommitted
stem
cells
or
adipogenic
precursor
differentiate
into
adipocytes,
most
abundant
cell
type
adipose
tissue.
Studies
examining
chromatin
modification
during
adipogenesis
have
provided
further
understanding
molecular
blueprint
that
controls
onset
differentiation.
Unlike
histone
acetylation,
methylation
has
context
dependent
effects
on
activity
transcribed
region
DNA,
with
individual
combined
marks
different
residues
providing
distinct
signals
for
gene
expression.
Over
half
42
methyltransferases
identified
in
mammalian
been
investigated
their
role
adipogenesis,
but
across
large
body
literature
available,
there
lack
clarity
over
potential
correlations
emerging
patterns
among
players.
In
this
review,
we
will
summarize
important
findings
from
studies
published
past
15
years
including
both
protein
arginine
(PRMTs)
and
lysine
(KMTs).
We
reveal
PRMT1/4/5,
H3K4
KMTs
(MLL1,
MLL3,
MLL4,
SMYD2
SET7/9)
H3K27
(EZH2)
all
play
positive
roles
while
PRMT6/7
H3K9
(G9a,
SUV39H1,
SUV39H2,
SETDB1)
negative
adipogenesis.
Medicina,
Год журнала:
2024,
Номер
60(6), С. 888 - 888
Опубликована: Май 28, 2024
Chronic
kidney
disease
(CKD)
is
characterized
by
persistent
dysfunction,
ultimately
resulting
in
end-stage
renal
(ESRD).
Renal
fibrosis
a
crucial
pathological
feature
of
CKD
and
ESRD.
However,
there
no
effective
treatment
for
this
condition.
Despite
the
complex
molecular
mechanisms
involved
fibrosis,
increasing
evidence
highlights
role
histone
modification
its
regulation.
The
reversibility
modifications
offers
promising
avenues
therapeutic
strategies
to
block
or
reverse
fibrosis.
Therefore,
comprehensive
understanding
regulatory
implications
may
provide
novel
insights
into
more
safer
approaches.
This
review
recent
advances
particularly
methylation
acetylation.
aim
explore
potential
as
targets
treating
Genes & Development,
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 12, 2024
Monomethylation
of
lysine
20
histone
H4
(H4K20me1)
is
catalyzed
by
Set8
and
thought
to
play
important
roles
in
many
aspects
genome
function
that
are
mediated
H4K20me
binding
proteins.
We
interrogated
this
model
a
developing
animal
comparing
parallel
the
transcriptomes
null
,
K20R/A
l(3)mbt
mutant
Drosophila
melanogaster
.
found
gene
expression
profiles
K20A
K20R
larvae
markedly
different
than
despite
similar
reductions
H4K20me1.
cells
have
severely
disrupted
transcriptome
fail
proliferate
vivo,
but
these
phenotypes
not
recapitulated
mutation
K20
indicating
developmental
defects
animals
largely
due
H4K20me1-independent
effects
on
expression.
Furthermore,
H4K20me1
protein
L(3)mbt
recruited
transcription
start
sites
most
genes
independently
even
though
bound
high
levels
Moreover,
both
bind
purified
H4K20R
nucleosomes
vitro.
conclude
changes
mutants
cannot
be
explained
loss
or
chromatin
therefore
does
large
role
Cell Reports,
Год журнала:
2024,
Номер
43(9), С. 114680 - 114680
Опубликована: Авг. 24, 2024
The
activation
of
the
zygotic
genome
constitutes
an
essential
process
during
early
embryogenesis
that
determines
overall
progression
embryonic
development.
Zygotic
(ZGA)
is
tightly
regulated,
involving
a
delicate
interplay
activators
and
repressors,
to
precisely
control
timing
spatial
pattern
gene
expression.
While
regulators
ZGA
vary
across
species,
they
accomplish
comparable
outcomes.
Recent
studies
have
shed
light
on
unanticipated
roles
components
both
after
ZGA.
Moreover,
different
seem
acquired
unique
functional
modalities
manifest
their
regulatory
potential.
In
this
review,
we
explore
these
observations
assess
whether
are
simply
anecdotal
or
contribute
broader
framework
employs
versatile
means
arrive
at
conserved
outcome.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 31, 2025
Abstract
Transcription
factors
are
speculated
to
play
crucial
roles
in
adaptive
evolution.
Using
ortholog
replacement
of
essential
transcription
(eTFs)
from
other
yeast
species,
we
investigated
how
eTFs
can
change.
Several
orthologs
could
not
fully
complement
Saccharomyces
cerevisiae
mutants,
indicating
that
functions
or
interactions
these
have
changed,
rendering
them
incompatible.
We
further
characterized
TFIIIC,
a
fast-evolving
protein
complex
assists
RNA
polymerase
III-mediated
transcription,
which
exhibited
complete
partial
incompatibility
several
subunits.
In
the
orthologous
Tfc7-replacement
line,
binding
TFIIIC
tRNA
genes
was
reduced,
yet
abundance
severely
affected.
However,
chromosomes
cells
were
often
mis-segregated
during
mitosis
and
their
fitness
reduced
spindle
checkpoint
mutant.
Our
chromatin-immunoprecipitation
experiments
uncovered
unstable
results
defective
cohesion
loading,
leading
chromosome
mis-segregation.
Swapping
highly
divergent
C-terminal
domain
Tfc7
rescued
its
interaction
with
Tfc1
cell
fitness,
supporting
is
caused
by
altered
between
reveal
distinct
well-studied
complex.