A. 8q24 amplification and human cancer:

Large scale genomic amplifications are among the most common
genetic lesions in cancer. Among the rare, but recurrent genomic
amplifications found in many solid tumors is the genomic locus
8q24, which contains the proto-oncogene c-MYC. Although the
majority of the studies involving 8q24 amplification in cancer
have focused on the role of the proto-oncogene c-MYC, it is
now evident that c-MYC alone cannot contribute to the aggressive
phenotype of the tumors and poor outcome of the patients.
The mouse models harboring c-myc transgene develop cancer
after a long latency and often require additional genetic lesions.
Recent studies strongly suggest that other genes present in the
8q24 amplicon are potentially important players in addition to the
proto-oncogene c-MYC, and may contribute directly to the outcome
of patients harboring the large-scale genomic rearrangement involving
8q24 amplification. Therefore, understanding the full extent of the
oncogenic effects of 8q24 amplification is critical to the development
of more effective and targeted therapies for breast cancer patients
that exhibit this genetic aberration.

Therefore, though c-MYC is the likely oncogene in 8q24 amplicon,
we suspect that it alone is not sufficient to result in the poor prognosis
seen in the cancer patients with the 8q24 amplification. We hypothesize
that additional genes in the amplicon contribute substantially to the
mammary tumor initiation and/or aggressive progression of neoplasia.
We will use chromosome engineering technology in mouse embryonic
stem cells to establish mouse strains containing amplification of a
genomic region similar to the human 8q24 amplicon, as well as strains
with increased copies of c-Myc only. This study will to accurately mimic
the human mutations involving 8q24 amplification and breast cancer.
We expect these models to contribute directly in understanding the
causal nature of the amplification in tumorigenesis and illuminate the
underlying genetic mechanism that would accelerate therapeutic
interventions for cancer patients.

B. Functional Identification and Analysis of Copy Number Variation in Schizophrenia

Schizophrenia is a debilitating psychiatric illness which affects over 1% of the world’s population. The last few years have seen tremendous advances made in deciphering the underlying genetic causes that may contribute to schizophrenia. Particularly, multiple studies suggest that copy number variation (CNV), or the gain and loss of large chunks of DNA, at distinct loci of the human genome may primarily contribute to the pathology of schizophrenia. These studies emphasize the obvious next step: developing models harboring similar genetic mutations, in order to functionally analyze the consequence of such genetic aberrations. Here I propose to develop mouse models harboring genetic CNVs found in schizophrenia patients. Specifically, genetically engineered mouse models will be generated containing similar mutations found in human schizophrenia patients harboring deletions in 1q21.1 and 15q13.3, two loci reported to be associated with rare but highly penetrant CNV in schizophrenia . Characterization of these mice will contribute to further understanding of the disease, leading to better therapeutics for the afflicted.

C. Functional analysis of the role of chd5 in tumorigenesis

An emerging theme in cancer biology is the role of chromatin structure in tumorigenesis. Though the human genome has roughly thirty thousand genes, only a fraction of those are expressed at any given time. How specific regions of the DNA are regulated is a subject of intense research. The major factors that contribute to chromatin packaging and DNA accessibility are 1) chemical modifications to the DNA, mainly the methylation of the Cytosine residue of the CpG islands, 2) the modifications to the histone tails, 3) the chromatin related proteins which establishes, reads and sometimes erases the above epigenetic marks, and 4) the chromatin remodeling proteins that control the chromatin conformation and dynamics. These factors, often in combination, lay down the ground rules for the epigenetic regulation of gene expression. Subsequently, they have profound effects on the cellular memory and cell fate, including that of the stem cell pool. Aberrant epigenetic changes, alone, or in conjunction with genetic abnormalities (mutations in the primary sequence of the DNA), lead to neoplastic transformation and progression. A major initiative in cancer research is to understand the daunting complexity this process, and to identify the major players whose roles are critical in maintaining homeostasis. 

We had recently discovered Chromodomain helicase DNA binding protein 5 (CHD5), an ATP-dependent chromatin-remodeling protein, as a tumor suppressor. CHD5 maps to Human 1p36.31, a region frequently deleted in many human cancers. We found that Chd5 positively regulates the p16Ink4a-Rb and p19Arf-p53 pathways, which provided the mechanism of tumor suppression. We further found that loss of CHD5 co-relates with primary gliomas. Subsequently, multiple independent study found CHD5 to be deleted or mutated in breast cancer, AML and neuroblastoma. Loss of CHD5 expression by hypermethylation of its promoter has been reported in neuroblastoma and also in gliomas and breast and colorectal cancer. The above studies have set the ground to carry out a more thorough analysis of the role of CHD5 in tumorigenesis. This will require developing new mouse models in which Chd5 is inactivated in the germline, and/or conditionally in a tissue specific manner. The fact that Chd5 belongs to the chromodomain containing chromatin remodeling gene family (CHD), it is expected that it will play an important role in configuring the chromatin landscape as an essential mechanism of its tumor suppressive function. Also, a tantalizing possibility is that the tumor suppression is mediated by Chd5’s ability to dictate the outcome of stem cell differentiation. These studies will lead to design of more targeted and effective therapeutic strategies against cancer

The Bagchi Lab is interested in developing functional genetic models of human diseases, namely cancer and schizophrenia. They are particularly interested in understanding the effect of the genomic structural variants associated with these diseases. Recurrent genomic deletions and amplifications have been a hallmark of many cancers. Similarly, the role of genomic copy number variation (CNV) in neurological diseases is coming under sharp focus after being implicated in a number of genome wide association studies. However, delineating the physiological effects of these structural variants has remained a challenge due to the lack of proper in vivo model system. We take advantage of genetically engineered mouse models to address this problem. They use chromosome engineering, a technique that combines Cre/loxP and gene targeting in mouse embryonic stem (ES) cells to create these strains. This technology allows them to generate mice harboring large deletions and duplications often associated with cancer and schizophrenia.

The Bagchi Lab is also interested in the role of the chromatin in cancer. The chromatin provides an additional layer of control to the regulatory components encoded by the DNA for proper gene expression in a cell. How the chromatin remodels in response to cellular cues is pivotal to the final outcome of the cell. Importantly, chromatin influences cellular differentiation. They hypothesize that malignant transformation of cell is partly due to improper cellular differentiation and collapse of a proper chromatin remodeling machinery, leading to activation of agents of transformation. Recently they identified Chromodomain helicase DNA binding protein (CHD5), a chromatin remodeling gene, as a tumor suppressor. CHD5 is located in Hu 1p36.3, a locus frequently deleted in many cancers. They are now investigating the molecular mechanism of tumor suppression by CHD5.

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Selected Publications:

Stark KL*, Xu B*, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Mills AA, Karayiorgou M, Gogos JA. Altered brain microRNA biogenesis in mice deficient for the 22q11 region contributes to behavioral and neuronal development deficits. Nature Genetics, 2008; 40:751-760. Advance online publication 11 May 2008 (DOI :10.1038/ng.138). (* Equal authorship).

Bagchi A, Mills AA. The Quest for the 1p36 Tumor Suppressor. Cancer Research, 2008; 68:2551-2556.

Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D, Bredel M, Vogel H, Mills AA. CHD5 is a tumor suppressor at Human 1p36. Cell, 2007; 128:459-475.

Mandal P, Bagchi A, Bhattacharya A, Bhattacharya S An Entamoeba histolytica LINE/SINE Pair Inserts at Common Target Sites Cleaved by the Restriction Enzyme-Like LINE-Encoded Endonuclease. Euk. Cell, 2004; 3:170-179.

Sharma R*, Bagchi A*, Bhattacharya S, Bhattacharya A. Characterization of a Retrotransposon like element in Entamoeba histolytica. Mol. Biochem.Parasitol, 2001; 116:45-53. (*Equal authorship).

Sharma R, Bagchi A, Bhattacharya S, Bhattacharya A. Characterization of Retrotransposon-like repetitive DNA in Entamoeba histolytica Arch Med Res. 2000; 31(4 Suppl):S266-8.
 
Bhattacharya A, Satish S, Bagchi A, Bhattacharya S. The Genome of Entamoeba histolytica. Int J Parasitol 2000; 30:401-410.

Bagchi A, Bhattacharya A, Bhattacharya S. Lack of a chromosomal copy of the circular rDNA plasmid of Entamoeba histolytica. Int J Parasitol 1999;29:1775-1783.


To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed
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