ACS Synthetic Biology,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 14, 2024
Enhancers
are
central
for
the
regulation
of
metazoan
transcription
but
have
proven
difficult
to
study,
primarily
due
a
myriad
interdependent
variables
shaping
their
activity.
Consequently,
synthetic
biology
has
emerged
as
main
approach
dissecting
mechanisms
enhancer
function.
We
start
by
reviewing
simple
highly
parallel
reporter
assays,
which
been
successful
in
quantifying
complexity
activator/coactivator
at
enhancers.
then
describe
studies
that
examine
how
enhancers
function
genomic
context
and
combination
with
other
enhancers,
revealing
they
activate
genes
through
variety
different
mechanisms,
working
together
system.
Here,
we
focus
on
can
quantify
dynamics
time.
end
considering
consequences
having
many
within
'local
environment',
believe
leads
correlated
gene
expression
likely
reports
general
principles
biology.
Molecular Cell,
Год журнала:
2023,
Номер
83(3), С. 373 - 392
Опубликована: Янв. 23, 2023
Uncovering
the
cis-regulatory
code
that
governs
when
and
how
much
each
gene
is
transcribed
in
a
given
genome
cellular
state
remains
central
goal
of
biology.
Here,
we
discuss
major
layers
regulation
influence
transcriptional
outputs
are
encoded
by
DNA
sequence
context.
We
first
transcription
factors
bind
specific
sequences
dosage-dependent
cooperative
manner
then
proceed
to
cofactors
facilitate
factor
function
mediate
activity
modular
elements
such
as
enhancers,
silencers,
promoters.
consider
complex
poorly
understood
interplay
these
diverse
within
regulatory
landscapes
its
relationships
with
chromatin
states
nuclear
organization.
propose
mechanistically
informed,
quantitative
model
integrates
multiple
will
be
key
ultimately
cracking
code.
Developmental Cell,
Год журнала:
2023,
Номер
58(19), С. 1898 - 1916.e9
Опубликована: Авг. 8, 2023
Chromatin
accessibility
is
integral
to
the
process
by
which
transcription
factors
(TFs)
read
out
cis-regulatory
DNA
sequences,
but
it
difficult
differentiate
between
TFs
that
drive
and
those
do
not.
Deep
learning
models
learn
complex
sequence
rules
provide
an
unprecedented
opportunity
dissect
this
problem.
Using
zygotic
genome
activation
in
Drosophila
as
a
model,
we
analyzed
high-resolution
TF
binding
chromatin
data
with
interpretable
deep
performed
genetic
validation
experiments.
We
identify
hierarchical
relationship
pioneer
Zelda
involved
axis
patterning.
consistently
pioneers
proportional
motif
affinity,
whereas
patterning
augment
contexts
where
they
mediate
enhancer
activation.
conclude
occurs
two
tiers:
one
through
pioneering,
makes
enhancers
accessible
not
necessarily
active,
second
when
correct
combination
of
leads
Developmental Cell,
Год журнала:
2023,
Номер
58(1), С. 51 - 62.e4
Опубликована: Янв. 1, 2023
Developmental
enhancers
bind
transcription
factors
and
dictate
patterns
of
gene
expression
during
development.
Their
molecular
evolution
can
underlie
phenotypical
evolution,
but
the
contributions
evolutionary
pathways
involved
remain
little
understood.
Here,
using
mutation
libraries
in
Drosophila
melanogaster
embryos,
we
observed
that
most
point
mutations
developmental
led
to
changes
levels
rarely
resulted
novel
outside
native
pattern.
In
contrast,
random
sequences,
often
acting
as
enhancers,
drove
across
a
range
cell
types;
sequences
including
motifs
for
with
pioneer
activity
acted
even
more
frequently.
Our
findings
suggest
phenotypic
landscapes
are
constrained
by
enhancer
architecture
chromatin
accessibility.
We
propose
existing
is
limited
its
capacity
generate
phenotypes,
whereas
de
novo
elements
primary
source
novelty.
Genes & Development,
Год журнала:
2023,
Номер
37(5-6), С. 218 - 242
Опубликована: Март 1, 2023
Pioneer
transcription
factors
are
thought
to
play
pivotal
roles
in
developmental
processes
by
binding
nucleosomal
DNA
activate
gene
expression,
though
mechanisms
through
which
pioneer
remodel
chromatin
remain
unclear.
Here,
using
single-cell
transcriptomics,
we
show
that
endogenous
expression
of
neurogenic
factor
ASCL1,
considered
a
classical
factor,
defines
transient
population
progenitors
human
neural
differentiation.
Testing
ASCL1's
function
knockout
model
define
the
unbound
state,
found
ASCL1
drives
progenitor
differentiation
Molecular Cell,
Год журнала:
2023,
Номер
84(2), С. 194 - 201
Опубликована: Ноя. 27, 2023
In
eukaryotic
genomes,
transcriptional
machinery
and
nucleosomes
compete
for
binding
to
DNA
sequences;
thus,
a
crucial
aspect
of
gene
regulatory
element
function
is
modulate
chromatin
accessibility
transcription
factor
(TF)
RNA
polymerase
binding.
Recent
structural
studies
have
revealed
multiple
modes
TF
engagement
with
nucleosomes,
but
how
initial
"pioneering"
results
in
steady-state
further
II
(RNAPII)
has
been
unclear.
Even
less
well
understood
distant
sites
open
interact
one
another,
such
as
when
developmental
enhancers
activate
promoters
release
RNAPII
productive
elongation.
Here,
we
review
evidence
the
centrality
conserved
SWI/SNF
family
nucleosome
remodeling
complexes,
both
pioneering
mediating
enhancer-promoter
contacts.
Consideration
unwrapping
ATP
hydrolysis
activities
together
their
architectural
features,
may
reconcile
occupancy
rapid
dynamics
observed
by
live
imaging.
