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KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.
[kabuki syndrome]
KMT
2
D
(
lysine
(
K
)
-
specific
methyltransferase
2
D
)
,
formerly
named
MLL
2
(
myeloid
/
lymphoid
or
mixed
-lineage
leukemia
2
,
also
known
as
ALR
/
MLL
4
)
,
is
a
histone
methyltransferase
that
plays
an
important
role
in
regulating
gene
transcription
.
In
particular
,
it
targets
histone
H
3
lysine
4
(
H
3
K
4
)
,
whose
methylations
serve
as
a
gene
activation
mark
.
Recently
,
KMT
2
D
has
emerged
as
one
of
the
most
frequently
mutated
genes
in
a
variety
of
cancers
and
in
other
human
diseases
,
including
lymphoma
,
medulloblastoma
,
gastric
cancer
,
and
Kabuki
syndrome
.
Mutations
in
KMT
2
D
identified
thus
far
point
to
its
loss
-of-function
in
pathogenesis
and
suggest
its
role
as
a
tumor
suppressor
in
various
tissues
.
To
determine
the
effect
of
a
KMT
2
D
deficiency
on
neoplastic
cells
,
we
used
homologous
recombination-
and
nuclease-mediated
gene
editing
approaches
to
generate
a
panel
of
isogenic
colorectal
and
medulloblastoma
cancer
cell
lines
that
differ
with
respect
to
their
endogenous
KMT
2
D
status
.
We
found
that
a
KMT
2
D
deficiency
resulted
in
attenuated
cancer
cell
proliferation
and
defective
cell
migration
.
Analysis
of
histone
H
3
modifications
revealed
that
KMT
2
D
was
essential
for
maintaining
the
level
of
global
H
3
K
4
monomethylation
and
that
its
enzymatic
SET
domain
was
directly
responsible
for
this
function
.
Furthermore
,
we
found
that
a
majority
of
KMT
2
D
binding
sites
are
located
in
regions
of
potential
enhancer
elements
.
Together
,
these
findings
revealed
the
role
of
KMT
2
D
in
regulating
enhancer
elements
in
human
cells
and
shed
light
on
the
tumorigenic
role
of
its
deficiency
.
Our
study
supports
that
KMT
2
D
has
distinct
roles
in
neoplastic
cells
,
as
opposed
to
normal
cells
,
and
that
inhibiting
KMT
2
D
may
be
a
viable
strategy
for
cancer
therapeutics
.
Diseases
Validation
Diseases presenting
"defective cell migration"
symptom
kabuki syndrome
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