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HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression.
[hirschsprung disease]
RET
gene
is
crucial
for
the
development
of
enteric
nervous
system
,
and
dys-regulation
of
RET
expression
causes
Hirschsprung
disease
.
HOXB
5
regulates
RET
transcription
,
and
perturbations
in
transcriptional
regulation
by
HOXB
5
caused
reduced
RET
expression
and
defective
enteric
nervous
system
development
in
mice
.
The
mechanisms
by
which
HOXB
5
regulate
RET
transcription
are
unclear
.
Thus
,
unraveling
the
regulatory
mechanisms
of
HOXB
5
on
RET
transcription
could
lead
to
a
better
understanding
of
the
etiology
of
Hirschsprung
disease
.
In
this
study
,
we
identified
and
confirmed
HOXB
5
binding
to
the
multi-species
conserved
sequence
(
MCS
+
9
.
7
)
in
the
first
intron
of
the
RET
gene
.
We
developed
a
RET
mini-
gene
reporter
system
,
and
showed
that
MCS
+
9
.
7
enhanced
HOXB
5
trans-activation
from
RET
promoter
in
human
neuroblastoma
SK-N-SH
cells
and
in
chick
embryos
.
The
deletion
of
HOXB
5
binding
site
interfered
with
HOXB
5
trans-activation
.
Furthermore
,
transfection
of
HOXB
5
induced
endogenous
RET
transcription
,
enhanced
the
co
-precipitation
of
TATA-box
binding
protein
with
the
transcription
start
site
of
RET
,
and
induced
histone
H
3
K
4
trimethylation
in
chromatin
regions
upstream
and
downstream
of
RET
transcription
start
site
.
In
conclusion
,
(
i
)
HOXB
5
physically
interacted
with
MCS
+
9
.
7
and
enhanced
RET
transcription
,
(
ii
)
HOXB
5
altered
chromatin
conformation
and
histone
modification
of
RET
locus
,
which
could
facilitate
the
formation
of
transcription
complex
,
and
enhance
RET
transcription
,
(
iii
)
expression
of
RET
was
mediated
by
a
complex
regulatory
network
of
transcription
factors
functioning
in
a
synergistic
,
additive
and
/
or
independent
manners
.
Hence
,
dys-regulation
of
RET
expression
by
HOXB
5
could
result
in
insufficient
RET
expression
and
Hirschsprung
disease
.
Diseases
Validation
Diseases presenting
"altered chromatin conformation and histone modification"
symptom
hirschsprung disease
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