1: Mol Cell Biol. 2005 May;25(10):3997-4009. 

MyoD targets chromatin remodeling complexes to the myogenin locus prior to
forming a stable DNA-bound complex.

de la Serna IL, Ohkawa Y, Berkes CA, Bergstrom DA, Dacwag CS, Tapscott SJ,
Imbalzano AN.

University of Massachusetts Medical School, Department of Cell Biology, 55 Lake
Avenue North, Worcester, MA 01655, USA.

The activation of muscle-specific gene expression requires the coordinated
action of muscle regulatory proteins and chromatin-remodeling enzymes.
Microarray analysis performed in the presence or absence of a dominant-negative
BRG1 ATPase demonstrated that approximately one-third of MyoD-induced genes were
highly dependent on SWI/SNF enzymes. To understand the mechanism of activation,
we performed chromatin immunoprecipitations analyzing the myogenin promoter. We
found that H4 hyperacetylation preceded Brg1 binding in a MyoD-dependent manner
but that MyoD binding occurred subsequent to H4 modification and Brg1
interaction. In the absence of functional SWI/SNF enzymes, muscle regulatory
proteins did not bind to the myogenin promoter, thereby providing evidence for
SWI/SNF-dependent activator binding. We observed that the homeodomain factor
Pbx1, which cooperates with MyoD to stimulate myogenin expression, is
constitutively bound to the myogenin promoter in a SWI/SNF-independent manner,
suggesting a two-step mechanism in which MyoD initially interacts indirectly
with the myogenin promoter and attracts chromatin-remodeling enzymes, which then
facilitate direct binding by MyoD and other regulatory proteins.

PMID: 15870273 [PubMed - indexed for MEDLINE]


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2: Leukemia. 2005 May;19(5):806-13. 

Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion
proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic
leukemia.

Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M,
Hunger SP.

Department of Pediatrics, University of Florida College of Medicine and the
University of Florida Shands Cancer Center, Gainesville, FL 32610, USA.

We analyzed the TS-2 acute lymphoblastic leukemia (ALL) cell line that contains
a t(1;19)(q23;p13.3) but lacks E2A-PBX1 fusion typically present in leukemias
with this translocation. We found that the t(1;19) in TS-2 fuses the 19p13 gene
DAZAP1 (Deleted in Azoospermia-Associated Protein 1) to the 1q23 gene MEF2D
(Myocyte Enhancer Factor 2D), leading to expression of reciprocal in-frame
DAZAP1/MEF2D and MEF2D/DAZAP1 transcripts. MEF2D is a member of the MEF2 family
of DNA binding proteins that activate transcription of genes involved in control
of muscle cell differentiation, and signaling pathways that mediate response to
mitogenic signals and survival of neurons and T-lymphocytes. DAZAP1 is a novel
RNA binding protein expressed most abundantly in the testis. We demonstrate that
MEF2D/DAZAP1 binds avidly and specifically to DNA in a manner indistinguishable
from that of native MEF2D and is a substantially more potent transcriptional
activator than MEF2D. We also show that DAZAP1/MEF2D is a sequence-specific
RNA-binding protein. MEF2D has been identified as a candidate oncogene in murine
retroviral insertional mutagenesis studies. Our data implicate MEF2D in human
cancer and suggest that MEF2D/DAZAP1 and/or DAZAP1/MEF2D contribute to
leukemogenesis by altering signaling pathways normally regulated by wild-type
MEF2D and DAZAP1.

PMID: 15744350 [PubMed - indexed for MEDLINE]


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3: Cancer Sci. 2004 Jun;95(6):503-7. 

Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia
with t(1;19)(q23;p13).

Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, Inazawa J.

Department of Molecular Cytogenetics, Medical Research Institute, Graduate
School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.

The most common nonrandom translocation found among childhood pre-B acute
lymphoblastic leukemias (ALL) is t(1;19)(q23;p13), which frequently results in
fusion of E2A with PBX1. However, rare cases of childhood ALL and various other
hematological diseases with t(1;19) lack the E2A-PBX1 fusion. Analyzing a cell
line with pre-B-cell phenotype, TS-2, that carries t(1;19)(q23;p13) but lacks
the E2A-PBX1 fusion, we successfully cloned the breakpoints, which fell within
introns of MEF2D and DAZAP1. Both chimeric transcripts, MEF2D-DAZAP1 and
DAZAP1-MEF2D, whose sequences indicated in-frame fusions between MEF2D and
DAZAP1, were expressed in TS-2 cells and in bone-marrow cells of the patient
from whom the TS-2 was established. MEF2D-DAZAP1 and DAZAP1-MEF2D proteins were
both located in the nucleus, and MEF2D-DAZAP1 was able to form dimers with MEF2D
and HDAC4. In addition, exogenous expression of MEF2D-DAZAP1 and DAZAP1-MEF2D
promoted the growth of HeLa cells. Given the frequency of t(1;19) without the
E2A-PBX1 fusion in hematological malignancies, we suggest that MEF2D / DAZAP1
rearrangements might be involved in the pathogenesis of those diseases.

PMID: 15182431 [PubMed - indexed for MEDLINE]


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