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Synergistic activation of cardiac genes by myocardin and Tbx5.
[holt-oram syndrome]
Myocardial
differentiation
is
associated
with
the
activation
and
expression
of
an
array
of
cardiac
specific
genes
.
However
,
the
transcriptional
networks
that
control
cardiac
gene
expression
are
not
completely
understood
.
Myocardin
is
a
cardiac
and
smooth
muscle
-
specific
expressed
transcriptional
coactivator
of
Serum
Response
Factor
(
SRF
)
and
is
able
to
potently
activate
cardiac
and
smooth
muscle
gene
expression
during
development
.
We
hypothesize
that
myocardin
discriminates
between
cardiac
and
smooth
muscle
specific
genes
by
associating
with
distinct
co
-factors
.
Here
,
we
show
that
myocardin
directly
interacts
with
Tbx
5
,
a
member
of
the
T
-
box
family
of
transcription
factors
involved
in
the
Holt-
Oram
syndrome
.
Tbx
5
synergizes
with
myocardin
to
activate
expression
of
the
cardiac
specific
genes
atrial
natriuretic
factor
(
ANF
)
and
alpha
myosin
heavy
chain
(
α-
MHC
)
,
but
not
that
of
smooth
muscle
specific
genes
SM
22
or
smooth
muscle
myosin
heavy
chain
(
SM-MHC
)
.
We
found
that
this
synergistic
activation
of
shared
target
genes
is
dependent
on
the
binding
sites
for
Tbx
5
,
T
-
box
factor
-
Binding
Elements
(
TBEs
)
.
Myocardin
and
Tbx
5
physically
interact
and
their
interaction
domains
were
mapped
to
the
basic
domain
and
the
coil
domain
of
myocardin
and
Tbx
5
,
respectively
.
Our
analysis
demonstrates
that
the
Tbx
5
G
8
0
R
mutation
,
which
leads
to
the
Holt-
Oram
syndrome
in
humans
,
failed
to
synergize
with
myocardin
to
activate
cardiac
gene
expression
.
These
data
uncover
a
key
role
for
Tbx
5
and
myocardin
in
establishing
the
transcriptional
foundation
for
cardiac
gene
activation
and
suggest
that
the
interaction
of
myocardin
and
Tbx
5
maybe
involved
in
cardiac
development
and
diseases
.
Diseases
Validation
Diseases presenting
"muscle myosin"
symptom
holt-oram syndrome
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