bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 16, 2024
Abstract
Immunomodulatory
imide
drugs
(IMiDs)
including
thalidomide,
lenalidomide,
and
pomalidomide,
can
be
used
to
induce
degradation
of
a
protein
interest
that
is
fused
short
zinc
finger
(ZF)
degron
motif.
These
IMiDs,
however,
also
endogenous
neosubstrates,
IKZF1
IKZF3.
To
improve
selectivity,
we
took
bump-and-hole
approach
design
screen
bumped
IMiD
analogs
against
8380
ZF
mutants.
This
yielded
analog
induces
efficient
mutant
degron,
while
not
affecting
other
cellular
proteins,
In
proof-of-concept
studies,
this
system
was
applied
TRIM28,
disease-relevant
with
no
known
small
molecule
binders.
We
anticipate
will
make
valuable
addition
the
current
arsenal
systems
for
use
in
target
validation.
One-Sentence
Summary
Engineered
zinc-finger-based
degrons
enable
targeted
induced
by
selective
molecular
glues.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2022,
Номер
unknown
Опубликована: Июль 8, 2022
Abstract
How
enhancers
control
target
gene
expression
over
long
genomic
distances
remains
an
important
unsolved
problem.
Here
we
studied
enhancer-promoter
contact
architecture
and
communication
by
integrating
data
from
nucleosome-resolution
maps,
nascent
transcription,
perturbations
to
transcription-associated
proteins
thousands
of
candidate
enhancers.
Contact
frequency
between
functionally
validated
pairs
was
most
enriched
near
the
+1
+2
nucleosomes
at
promoters,
indicating
that
functional
spend
time
in
close
physical
proximity.
Blocking
RNA
polymerase
II
(Pol
II)
caused
major
disruptions
contacts.
Paused
Pol
occupancy
enzymatic
activity
poly
(ADP-ribose)
1
(PARP1)
stabilized
Based
on
our
findings,
propose
updated
model
couples
transcriptional
dynamics
communication.
Communications Biology,
Год журнала:
2023,
Номер
6(1)
Опубликована: Авг. 4, 2023
Abstract
Investigating
gene
function
relies
on
the
efficient
manipulation
of
endogenous
expression.
Currently,
a
limited
number
tools
are
available
to
robustly
manipulate
expression
between
“on”
and
“off”
states.
In
this
study,
we
insert
63
bp
coding
sequence
T3H38
ribozyme
into
3’
untranslated
region
(UTR)
C.
elegans
genes
using
CRISPR/Cas9
technology,
which
reduces
nearly
undetectable
level
generated
loss-of-function
phenotypes
similar
that
genetic
null
animals.
To
achieve
conditional
knockout,
cassette
loxP
-flanked
transcriptional
termination
signal
is
inserted
UTR
genes,
eliminates
spatially
or
temporally
via
controllable
Cre
recombinase.
Conditional
turn-on
can
be
achieved
by
either
injecting
morpholino,
blocks
self-cleavage
activity
recombinase
remove
ribozyme.
Together,
our
results
demonstrate
these
ribozyme-based
efficiently
both
in
space
time
expand
toolkit
for
studying
functions
genes.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 16, 2024
Abstract
Immunomodulatory
imide
drugs
(IMiDs)
including
thalidomide,
lenalidomide,
and
pomalidomide,
can
be
used
to
induce
degradation
of
a
protein
interest
that
is
fused
short
zinc
finger
(ZF)
degron
motif.
These
IMiDs,
however,
also
endogenous
neosubstrates,
IKZF1
IKZF3.
To
improve
selectivity,
we
took
bump-and-hole
approach
design
screen
bumped
IMiD
analogs
against
8380
ZF
mutants.
This
yielded
analog
induces
efficient
mutant
degron,
while
not
affecting
other
cellular
proteins,
In
proof-of-concept
studies,
this
system
was
applied
TRIM28,
disease-relevant
with
no
known
small
molecule
binders.
We
anticipate
will
make
valuable
addition
the
current
arsenal
systems
for
use
in
target
validation.
One-Sentence
Summary
Engineered
zinc-finger-based
degrons
enable
targeted
induced
by
selective
molecular
glues.
