Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety of Cancers

Article (PDF Available)inThe American Journal of Human Genetics 65(5):1342-8 · December 1999with33 Reads
DOI: 10.1086/302639 · Source: PubMed
Abstract
Biallelic, truncating mutations of the hSNF5/INI1 gene have recently been documented in malignant rhabdoid tumor (MRT), one of the most aggressive human cancers. This finding suggests that hSNF5/INI1 is a new tumor-suppressor gene for which germline mutations might predispose to cancer. We now report the presence of loss-of-function mutations of this gene in the constitutional DNA from affected members but not from healthy relatives in cancer-prone families. Furthermore, a constitutional mutation is documented in a patient with two successive primary cancers. In agreement with the two-hit model, the wild-type hSNF5/INI1 allele is deleted in the tumor DNA from mutation carriers. In all tested cases, DNA from parents demonstrated normal hSNF5/INI1 sequences, therefore indicating the de novo occurrence of the mutation, which was shown to involve the maternal allele in one case and the paternal allele in two other cases. These data indicate that constitutional mutation of the hSNF5/INI1 gene defines a new hereditary syndrome predisposing to renal or extrarenal MRT and to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor. This condition, which we propose to term "rhabdoid predisposition syndrome," may account for previous observations of familial and multifocal cases of the aforementioned tumor types. It could also provide the molecular basis for cases of Li-Fraumeni syndrome without p53 germline mutations.
Am. J. Hum. Genet. 65:1342–1348, 1999
1342
Constitutional Mutations of the hSNF5/INI1 Gene Predispose to a Variety
of Cancers
Nicolas Se´venet,
1
Eammon Sheridan,
2
Daniel Amram,
3
Pascale Schneider,
4
Rupert Handgretinger,
5
and Olivier Delattre
1
1
Laboratoire de Pathologie Mole´culaire des Cancers, INSERM U 509, Institut Curie, Paris;
2
Department of Clinical Genetics, St. James’s
University Hospital, Leeds;
3
Pe´diatrie Ne´onatale, Hoˆpital Caremeau, ˆmes, France;
4
Pe´diatrie et Ge´ne´tique Me´dicale, Hoˆ pital Charles
Nicolle, Rouen; and
5
Universita¨t Kinderklinik, Tu¨bingen, Germany
Summary
Biallelic, truncating mutations of the hSNF5/INI1 gene
have recently been documented in malignant rhabdoid
tumor (MRT), one of the most aggressive human can-
cers. This finding suggests that hSNF5/INI1 is a new
tumor-suppressor gene for which germline mutations
might predispose to cancer. We now report the presence
of loss-of-function mutations of this gene in the consti-
tutional DNA from affected members but not from
healthy relatives in cancer-prone families. Furthermore,
a constitutional mutation is documented in a patient
with two successive primary cancers. In agreement with
the two-hit model, the wild-type hSNF5/INI1 allele is
deleted in the tumor DNA from mutation carriers. In all
tested cases, DNA from parents demonstrated normal
hSNF5/INI1 sequences, therefore indicating the de novo
occurrence of the mutation, which was shown to involve
the maternal allele in one case and the paternal allele in
two other cases. These data indicate that constitutional
mutation of the hSNF5/INI1 gene defines a new hered-
itary syndrome predisposing to renal or extrarenal MRT
and to a variety of tumors of the CNS, including choroid
plexus carcinoma, medulloblastoma, and central prim-
itive neuroectodermal tumor. This condition, which we
propose to term “rhabdoid predisposition syndrome,”
may account for previous observations of familial and
multifocal cases of the aforementioned tumor types. It
could also provide the molecular basis for cases of Li-
Fraumeni syndrome without p53 germline mutations.
Received July 9, 1999; accepted for publication August 3, 1999;
electronically published October 5, 1999.
Address for correspondence and reprints: Dr. Olivier Delattre, La-
boratoire de Pathologie Mole´culaire des Cancers, INSERM U 509,
Institut Curie, 26 rue d’Ulm, 75248 Paris Cedex 05, France. E-mail:
delattre@curie.fr
q 1999 by The American Society of Human Genetics. All rights reserved.
0002-9297/1999/6505-0016$02.00
Introduction
Malignant rhabdoid tumor (MRT) was initially de-
scribed in the kidney, as an aggressive variant of Wilms
tumor (Beckwith and Palmer 1978). Subsequently, rhab-
doid phenotypes were observed in a variety of neoplasia
localized in the brain, the abdomen, or the soft tissue
(Parham et al. 1994; Wick et al. 1995; Rorke et al. 1996;
Burger et al. 1998). The observation of recurrent alter-
ations of chromosome 22 in both renal and extrarenal
MRTs has provided the first indication that these tumors
could share a common genetic basis and constitute a
distinct tumoral entity (Douglass et al. 1990; Biegel et
al. 1992, 1996; Schofield et al. 1996; Rosty et al. 1998;
White et al. 1999). Using a positional cloning strategy
aimed at the characterization of these chromosome 22
alterations, we recently identified hSNF5/INI1, a gene
encoding a member of the SWI/SNF ATP-dependent
chromatin-remodeling complex, as the target of recur-
rent loss-of-function alterations in renal and extrarenal
MRT (Kalpana et al. 1994; Muchardt et al. 1995; Ver-
steege et al. 1998; Wade and Wolffe 1999). The obser-
vation of biallelic, truncating mutations in tumors
strongly supported the hypothesis that hSNF5/INI1 is a
new tumor-suppressor gene consistently inactivated in
MRT. In addition to somatically acquired alterations,
constitutional mutations of this gene also have been ob-
served very recently in patients with MRT (Biegel et al.
1999).
To further delineate the spectrum of tumors with
hSNF5/INI1 inactivation and to gain insights into a pos-
sible predisposition syndrome associated with germline
mutations, we have screened a variety of neoplastic le-
sions, by direct sequencing or denaturing high-perform-
ance liquid chromatography (dHPLC) analysis of tumor
DNA (Underhill et al. 1997). Surprisingly, in addition
to MRTs, hSNF5/INI1 mutations were detected in most
choroid plexus carcinomas (CPCs), highly malignant tu-
mors arising from the cerebral ventricles, and in a subset
of medulloblastomas and central primitive neuroecto-
dermal tumors (PNETs) (Se´venet et al., in press). More-
over, during the course of this study, truncating muta-
Se´venet et al.: Constitutional Mutations of hSNF5/INI1 1343
tions were identified in the tumors of patients that had
individual or familial histories of cancer. Together with
previous reports of familial cases of MRT and of germ-
line mutations of hSNF5/INI1, this observation strongly
suggested that constitutional mutations of hSNF5/INI1
could predispose to cancer (Lynch et al. 1983; Biegel et
al. 1999). We now report the analysis of hSNF5/INI1-
gene mutation in those individuals or families with mul-
tiple cases of cancer.
Patients and Methods
Patients
Tumors were obtained either as frozen material stored
at 2807C or as paraffin-embedded tissue. Blood samples
from affected and unaffected family members were col-
lected. Informed consent was obtained from all individ-
uals or parents.
Mutation Analysis
DNA from blood and frozen tumor samples was ex-
tracted, by means of standard procedures, with phenol/
chloroform extraction and ammonium acetate/ethanol
precipitation. Paraffin-embedded fragments were depar-
affinized by xylene and were rinsed in ethanol prior to
DNA extraction by the QiaAmp Tissue Kit (Qiagen).
RNA was isolated from frozen samples by means of
Trizol reagent (GibcoBRL). For mutation detection,
dHPLC (denaturing high-performance liquid chroma-
tography) analysis using the Wave technology (Trans-
genomic) and direct sequencing were used.
In brief, for each tumor DNA, the nine hSNF5/INI1
exons were PCR amplified by means of primers localized
in flanking intronic sequences. In addition, the complete
hSNF5/INI1 transcript was reverse transcribed, and five
overlapping PCR products were analyzed. For dHPLC
analysis, PCR products were denatured for 10 min at
987C, were submitted to a gradual reannealing from
987C to 257C over a period of 40 min, were loaded onto
a DNAsep column, and were eluted, by means of an
acetonitrile gradient, at a defined melting temperature.
Wavemaker 1.2.2 software was used to predict both the
mean melting temperature of each PCR fragment and
the appropriate linear acetonitrile gradient necessary to
differentiate hetero- and homoduplexes. These condi-
tions were also evaluated experimentally by analysis of
the elution time at different temperatures (melting
curves) and by testing of the elution time of PCR prod-
ucts from known mutants (Versteege et al. 1998). The
start and end points of the gradient were adjusted ac-
cording to the size and the percentage of GC nucleotides
of each PCR fragment. Sequencing was performed on
purified PCR products by means of the BigDye Termi-
nator method (PE Biosystems) and 373A or 377 auto-
matic sequencers. The sequences of the intron-exon
boundaries can be retrieved at the EMBL database, and
the sequences of the primer pairs used for PCR, together
with the dHPLC conditions, can be found at our web
site at the Institut Curie.
Microsatellite Analysis
The loci used for haplotype determination have been
described elsewhere (Versteege et al. 1998). Analysis at
microsatellite loci was performed according to standard
procedure. In brief, 40 ng of DNA were amplified by
means of 6 pmol of each primer, by the GenAmp PCR
core kit (PE Biosystems). After an initial denaturation
at 967C for 2 min, 35 cycles of PCR were performed.
Each cycle consisted of denaturation at 967C for 30 s,
annealing at 557C for 30 s, and extension at 727C for
30s. Terminal extension was performed at 727C for 5
min. PCR products were denatured, migrated on a 6%
denaturing polyacrylamide gel, and then were trans-
ferred to a nylon N
1
membrane (Amersham Interna-
tional) and hybridized with a 3
0
end–labeled (CA)
12
probe. The membranes were then washed three times
with at room temperature and were subjected2 # SSC
to autoradiography.
Results
Analysis of hSNF5/INI1 Sequences in Cancer-Prone
Families
Three pedigrees with multiple cases of cancer dem-
onstrating the presence of a hSNF5/INI1 point mutation
in the tumor DNA and/or constitutional DNA of at least
one member of the family were further analyzed. Pedi-
gree 1 was characterized by two cases of CNS tumors:
an atypical teratoid and rhabdoid tumor (ATTR) and a
CPC, diagnosed at age 34 mo and 16 mo, respectively.
Analysis of the sequence of the hSNF5/INI1 gene of the
DNA of these two tumors demonstrated a deletion of
one G at codon 144 (bp 430), resulting in a frameshift
(fig. 1). The observation of the same mutation in these
two tumors strongly suggested that it was constitution-
ally inherited. Constitutional DNA from members of this
family were not available to confirm this hypothesis.
In pedigree 2, two of the four children died of ag-
gressive cancers at a very young age. In the first child,
a medulloblastoma with frontal metastasis was diag-
nosed at age 3 mo. The fourth child developed a con-
genital MRT of the soft tissues of the neck. DNA analysis
of the latter tumor demonstrated a CrT transition re-
sulting in a nonsense mutation at codon 158 (bp 472).
The constitutional DNA from this patient displayed het-
erozygosity of the same mutant allele. Conversely, this
mutation was not detected in the constitutional DNA of
the healthy parents and unaffected sisters (fig. 1). The
1344 Am. J. Hum. Genet. 65:1342–1348, 1999
Figure 1 Schematic representation of four pedigrees with mu-
tations of hSNF5/INI1. The results of the molecular analysis are shown
below each family member. Normal and italic characters indicate the
results of the analysis of constitutional DNA and tumor DNA, re-
spectively. N = normal sequence; a virgule (/) indicates that DNA was
not available for analysis. Mb = medulloblastoma; other abbreviations
are as defined in the text. The age (in years) of the healthy sibs is
indicated. In pedigree 4, the results of the DNA analysis of the two
tumors (T1 and T2) are given.
presence of the mutation at the constitutional and/or
tumor level could not be documented for child II.1, be-
cause of the absence of stored biological material. How-
ever, the association, in this family, of a germline mu-
tation in one sib (II.4) and of a rare CNS childhood
tumor in another (II.1) , is certainly not coincidental,
especially in light of our recent results showing that so-
matic mutations of hSNF5/INI1 can occur in medullob-
lastoma (Se´venet et al., in press).
Pedigree 3 was characterized by three cases of cancer,
including one CPC at age 4 mo and two ATTR, one at
age 2 mo and one at age 12 mo. Molecular analysis
revealed a deletion of one G at codon 197 (bp 591),
leading to a frameshift of the hSNF5/INI1 coding se-
quence, in all tested constitutional DNA and tumor
DNA from affected members. In contrast, DNA from
the healthy parents and from the three unaffected sibs
demonstrated wild-type hSNF5/INI1 sequences (fig. 1).
Analysis of hSNF5/INI1 in One Patient with Bifocal
Tumors
Constitutional DNA and tumor DNA from one pa-
tient with two successive tumors could be studied (fig.
1, pedigree 4); this patient was cured of a renal MRT
resected at age 5 mo, then developed a central PNET
10 years later. Given the distinct phenotypes of these
cancers and the long interval between their occurrences,
this latter neoplasm was most probably a second tumor,
rather than a late recurrence of the former. DNA from
the two tumors demonstrated the presence of the same
CrT transition, resulting in a nonsense mutation at co-
don 201 (bp 601). Constitutional DNA isolated from
normal renal tissue and from blood exhibited hetero-
zygosity for this mutation. Similar to what was observed
in pedigrees 2 and 3, the DNA from the unaffected par-
ents displayed wild-type sequences, indicating the de
novo occurrence of this mutation.
Loss of the Wild-Type Allele in Tumors
Three tumors displayed a high tumor-cell content,
compatible with loss-of-heterozygosity (LOH) analysis
at the hSNF5/INI1 locus. Indeed, comparison of the se-
quence profiles from constitutional DNA and tumor
DNA from these cases clearly documented the complete
loss of the wild-type hSNF5/INI1 allele in the tumor
DNA (fig. 2). These data therefore provided evidence for
a complete loss-of-function of hSNF5/INI1 in the tu-
mors arising in the context of a constitutional mutation.
Parental Origin of the Mutated Allele
Microsatellite analysis at seven chromosome 22q
polymorphic loci (D22S301, GCT10, D22S345,
D22S1164, D22S926, D22S421, and D22S429) ank-
ing the hSNF5/INI1 locus was performed on three
pedigrees. Segregation and LOH analyses enabled us
to determine the parental origin of lost and retained
alleles in the tumor DNA and to reconstitute mutated
and wild-type haplotypes. In pedigree 3, the mutation
in cases II.5 and II.6 is inherited from the mother,
which indicates the presence of a maternal mosaicism.
Unaffected daughter II.1 has inherited the other ma-
ternal allele, and unaffected sibs II.2 and II.3 display
crossing-over between maternal chromosomes exclud-
ing the hSNF5/INI1 mutation (fig. 3). The normal
sequence of hSNF5/INI1 in both broblast DNA and
blood DNA from the mother suggests that the mo-
saicism is restricted to her germinal lineage. A similar
approach was performed for pedigrees 2 and 4 and
showed that the mutation involved the paternal allele
(fig. 3). However, for pedigree 4, characterized by a
unique affected child, it could not be concluded
whether the mutation was inherited from the father
or occurred on the paternal chromosome at a post-
zygotic stage in the patient.
Discussion
The present report further strengthens the hypothesis
that hSNF5/INI1 is a tumor-suppressor gene, since it
fulfills the genetic features of this class of genes: biallelic,
somatic loss-of-function mutations in sporadic tumor
cases, and constitutional alterations causing a domi-
nantly inherited cancer-predisposition syndrome asso-
ciated with somatic loss of the wild-type allele in tumors
(Knudson 1996). We propose to term this hereditary
Se´venet et al.: Constitutional Mutations of hSNF5/INI1 1345
Figure 2 Loss of the wild-type hSNF5/INI1 allele in tumors. The results for the male child in pedigree 3 who had ATTR (II.6) and for
the patient in pedigree 4 who had bifocal tumors (II.1) are depicted. The normal sequences (N) are shown at the top; the constitutional sequences
(C) that demonstrate heterozygosity between wild-type and mutated alleles are shown below them. a, Case II.6 from pedigree 3. The sequence
of the ATTR DNA (T) shows the mutated 591delG allele with complete disappearance of the wild-type allele. b, Case II.1 from pedigree 4.
DNA from the two successive tumors (T1 [renal MRT] and T2 [central PNET]) demonstrates the presence of the 601T mutated allele and the
loss of the wild-type 601C allele. Therefore, in these three tumors, no functional allele of hSNF5/INI1 was retained.
condition, caused by constitutional hSNF5/INI1 muta-
tions, “rhabdoid predisposition syndrome” (RPS). At
present, the spectrum of tumors observed in RPS in-
cludes renal and extrarenal MRT, CPC, central PNET,
and medulloblastoma and fully overlaps with the spec-
trum of cancers that demonstrate acquired, biallelic mu-
tations of this gene (Se´venet et al., in press). The obser-
vation of loss-of-function mutations of hSNF5/INI1 in
these different neoplasia strongly suggests that they share
common pathways of oncogenesis and that they might
constitute a single family of tumors.
The present study suggests that the penetrance of this
syndrome is high at a very young age, since all first
neoplasia occurred at age
!3 years in mutation carriers
and since no hSNF5/INI1 mutation was detected in the
DNA of the 11 healthy sibs or parents who were ana-
lyzed. This high penetrance, together with the frequently
fatal outcome in affected members, is expected to ac-
count for the rarity of large pedigrees with transmission
of the mutation across multiple generations.
In all instances in which DNA from healthy parents
could be studied, it displayed a normal hSNF5/INI1 se-
quence, therefore demonstrating the de novo origin of
the mutation. Such new mutations can occur either pre-
zygotically, during oogenesis or spermatogenesis, or
postzygotically, during early steps of embryogenesis. Our
study documents that, in pedigree 3, the mutation was
inherited from the mother and probably occurred during
oogenesis, since both maternal-fibroblast DNA and ma-
ternal-blood DNA displayed normal hSNF5/INI1 se-
quences. In contrast, the mutation in pedigree 2 was
inherited from the father and thus probably arose during
spermatogenesis. In pedigree 4, the mutation also in-
volved the paternal allele; however, at present, the pre-
1346 Am. J. Hum. Genet. 65:1342–1348, 1999
Figure 3 Parental origin of the mutated allele. Haplotypes around the hSNF5/INI1 gene on chromosome 22 are displayed for pedigrees
2–4. Paternal and maternal haplotypes are indicated on the left and right, respectively. The seven microsatellite markers shown on the left are
included within a 3-cM region (Dib et al. 1996). “C” and “T” denote constitutional DNA and tumor DNA, respectively. The point mutations
of hSNF5/INI1 are depicted by red crosses. In pedigree 3, the mutation is carried by the maternal allele, whereas in pedigrees 2 and 4 it involves
the paternal allele.
or postzygotic step of its occurrence cannot be docu-
mented in this pedigree with a single child. The analysis
of sperm from the father might enable us to document
the presence of the mutation at the germinal level. Al-
though definitive conclusions cannot be drawn from
these cases, our study suggests that RPS de novo mu-
tations, like those of von Hippel-Lindau syndrome, do
not demonstrate the preferential or exclusive involve-
ment of the paternal allele, which is observed in other
cancer-predisposition syndromes, such as MEN2A,
MEN2B, neurofibromatosis type 1, and retinoblastoma
(Dryja et al. 1989; Zhu et al. 1989; Jadayel et al. 1990;
Carlson et al. 1994; Richards et al. 1995; Schuffenecker
et al. 1997).
The present study demonstrates that a predisposition
to a variety of cancer is linked to hSNF5/INI1 mutation.
This alteration probably provides the molecular basis
for familial and multifocal cases of the various tumors
that are part of the RPS spectrum that has been reported
elsewhere (Bonnin et al. 1984; Tijssen 1991; Fort et al.
1994; Matsumura et al. 1997; Chidambaram et al. 1998;
Moschovi et al. 1998; Parellada et al. 1998; Raila et al.
1998). In particular, since the spectrum of tumors ob-
served in RPS, especially brain tumors, largely overlaps
with that of Li-Fraumeni syndrome (LFS), a cancer-pre-
disposition syndrome frequently associated with p53
germline mutations, the possibility that a number of p53
gene mutation–negative LFS cases harbor hSNF5/INI1
mutations can now be tested (Kleihues et al. 1997; Varley
et al. 1997; Hisada et al. 1998).
Se´venet et al.: Constitutional Mutations of hSNF5/INI1 1347
Acknowledgments
This work was supported by grants from the Association
pour la Recherche contre le Cancer, the Institut Curie, the
Institut National de la Sante´ et de la Recherche Me´dicale, and
the Programme Hospitalier de Recherche Clinique. N.S. is the
recipient of a fellowship from the Ministe`re de l’Education
Nationale, de la Recherche et de la Technologie. We thank
Andre´ Nicolas for technical help, and we thank the following
clinicians for providing samples used in this study: A. Bor-
nemann, V. Costes, T. Klingebiel, A. Lacquerrie`re, G. Mar-
guerite, R. Meyermann, P. Ruck, N. Saran, and J.-P. Vannier.
Electronic-Database Information
Accession numbers and URLs for data in this article are as
follows:
EMBL database, http://www.ebi.ac.uk/cgi-bin/emblfetch (for
sequences of the intron-exon boundaries [Y17118-Y17126])
Institut Curie, http://www.curie.fr/sr/unites/u509 (for se-
quences of the primer pairs used for PCR together with the
dHPLC conditions)
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    • "Efforts to identify more effective treatments of CPC have been hindered by poor understanding of its pathogenesis. Germline deletion of hSNF5/INI1 or mutation of TP53 predisposes to CPC in humans (Garber et al., 1991; Malkin et al., 1990; Olivier et al., 2003; Sevenet et al., 1999; Tinat et al., 2009) and ablation of Tp53 and/or Rb function causes CPCs in mice (Brinster et al., 1984; Sáenz Robles et al., 1994). Deletion of PTEN has also been implicated in CPC, but activated oncogenes have not been described (Morigaki et al., 2012; Rickert et al., 2002; Ruland et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: Choroid plexus carcinomas (CPCs) are poorly understood and frequently lethal brain tumors with few treatment options. Using a mouse model of the disease and a large cohort of human CPCs, we performed a cross-species, genome-wide search for oncogenes within syntenic regions of chromosome gain. TAF12, NFYC, and RAD54L co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3 were identified as oncogenes that are gained in tumors in both species and required for disease initiation and progression. TAF12 and NFYC are transcription factors that regulate the epigenome, whereas RAD54L plays a central role in DNA repair. Our data identify a group of concurrently gained oncogenes that cooperate in the formation of CPC and reveal potential avenues for therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · May 2015
    • "Cases of familial-associated rhabdoid tumors are still uncommon but are rising in frequency. This suggests that either their incidence is increasing or that this condition is now more readily recognized and therefore increasingly diagnosed [18,41,42,96,9899100101102103104105108,111]. "
    [Show abstract] [Hide abstract] ABSTRACT: Abstract Rhabdoid tumors (RT), or malignant rhabdoid tumors (MRT), are amongst the most aggressive and lethal forms of human cancer. They can arise in any location in the body but are most commonly observed in the brain, where they are called atypical teratoid / rhabdoid tumors (AT/RT), and in the kidneys, where they are called rhabdoid tumors of the kidney (RTK). The vast majority of rhabdoid tumors present with a loss of function in the SMARCB1 gene, also known as INI1, BAF47 and hSNF5,, a core member of the SWI/SNF chromatin-remodeling complex. Recently, mutations in a second locus of the SWI/SNF complex, the SMARCA4 gene, also known as BRG1 were found in rhabdoid tumors with retention of SMARCB1 expression. Familial cases may occur in a condition known as rhabdoid tumor predisposition syndrome (RTPS). In RTPS, germline inactivation of one allele of a gene occurs. When the mutation occurs in the SMARCB1 gene, the syndrome is called RTPS1, and when the mutation occurs in the SMARCA4, gene it is called RTPS2. Children presenting with RTPS tend to develop tumors at a younger age, but the impact that germline mutation has on survival remains unclear. Adults who carry the mutation tend to develop multiple schwannomas. The diagnosis of RTPS should be considered in patients with RT, especially if they have multiple primary tumors and/or in individuals with a family history of RT. Because germline mutations result in an increased risk of carriers developing RT, genetic counseling for families with this condition is recommended.
    Full-text · Article · Dec 2014
    • "BAF47/INI1 plays a crucial role in orchestrating the balance between pluripotency and cell differentiation in embryonic stem cells [14]. Moreover, BAF47/INI1 is a tumor suppressor gene [15], since constitutive mutations have been associated with a strong predisposition to develop malignant rhabdoı¨drhabdoı¨d tumors, some of which could be of myogenic origin [16,17,18] . One consequence of BAF47/INI1 loss is the activation of gene expression programs that are associated with proliferation [19,20,21,22]. "
    [Show abstract] [Hide abstract] ABSTRACT: Myogenic terminal differentiation is a well-orchestrated process starting with permanent cell cycle exit followed by muscle-specific genetic program activation. Individual SWI/SNF components have been involved in muscle differentiation. Here, we show that the master myogenic differentiation factor MyoD interacts with more than one SWI/SNF subunit, including the catalytic subunit BRG1, BAF53a and the tumor suppressor BAF47/INI1. Downregulation of each of these SWI/SNF subunits inhibits skeletal muscle terminal differentiation but, interestingly, at different differentiation steps and extents. BAF53a downregulation inhibits myotube formation but not the expression of early muscle-specific genes. BRG1 or BAF47 downregulation disrupt both proliferation and differentiation genetic programs expression. Interestingly, BRG1 and BAF47 are part of the SWI/SNF remodeling complex as well as the N-CoR-1 repressor complex in proliferating myoblasts. However, our data show that, upon myogenic differentiation, BAF47 shifts in favor of N-CoR-1 complex. Finally, BRG1 and BAF47 are well-known tumor suppressors but, strikingly, only BAF47 seems essential in the myoblasts irreversible cell cycle exit. Together, our data unravel differential roles for SWI/SNF subunits in muscle differentiation, with BAF47 playing a dual role both in the permanent cell cycle exit and in the regulation of muscle-specific genes.
    Full-text · Article · Oct 2014
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