Aging

The biology of aging is one of the most rapidly developing areas in biomedical sciences. Insight into the molecular and cellular targets of the aging process would offer the unprecedented opportunity to postpone and prevent some, if not all, of its deteriorative aspects by preventive and therapeutic means. We are investigating causal factors and molecular mechanisms of aging with special focus on understanding the integrated genomic circuits that control mechanisms of aging and the dynamic network of genes that determines the physiology of an individual organism over time.

Areas of investigation include:

aging

Cancer Genetics

Cancer genetics investigates the processes by which multiple alterations occur in the genome of normal cells that lead to uncontrolled cell growth and proliferation. Such changes, that arises early and constitutes inheritable events, occur at level of the genome and the epigenome and result in permanent inheritable changes. Investigators within the Department of Genetics are actively working to decipher the complexity of such changes in various human cancer types and mouse models for cancer. Our final goals are to study basic mechanisms of cancer transformation, to identify novel biomarkers for personalized medicine and to provide targets for therapy.

Areas of investigation include:

  • Human retroviruses in evolution and their role in cancer initiation and progression (J. Lenz; G. Kalpana)
  • Epigenetic modifications including DNA methylation changes in human cancer, murine models for human cancer as well as histone modifications and chromatin remodeling (J. Greally; G. Kalpana; C. Montagna; S. Spivack)
  • Drug discovery and identification of novel biomarkers for early detection (G. Kalpana, C. Montagna, S. Spivack)
  • Role of genetic variation in cancer susceptibility (Y. Suh)
  • Cell competition to detect and suppress aneuploidy and genome damage (N. Baker)
cancer-genetics

Developmental Genetics

The development of an organism from a single cell to a fully formed and functional animal is an astonishing process. Patterning, morphogenesis, cell growth, and cell differentiation are in large part genetically controlled during organismal development. Department of Genetics faculty are studying several aspects of development using a range of organisms.

Areas of investigation include:

  • Development of the ear and pharyngeal apparatus, which gives rise to the craniofacial region, thymus, and cardiac outflow tract, in humans and mice (B. Morrow)
  • The extracellular signals that regulate forebrain development and adult neurogenesis in the mouse (J. Hebert)
  • Molecular mechanisms of heart development and congenital heart disease in mouse (B. Zhou)
  • Cell-cell signaling during neural/eye development (N. Baker)
  • Cell competition that selectively eliminates suboptimal cells from mixed populations (N. Baker)
  • Transcriptional regulation governing hormone signaling and neuronal development and function (J. Secombe)
developmental-genetics

Epigenomics

The new field of epigenomics studies heritable properties of the genome that are not encoded in the DNA sequence. These properties are now found to be propagated by molecular processes such as cytosine methylation, chromatin structure, post-translational modifications of histones, small RNA species, and histone variant deposition. These all lead to modifications in the transcriptional regulatory program, with effects to change gene expression in response to environmental influences and as part of disease pathogenesis.

Areas of investigation include:

epigenomics

Infectious Disease Genetics

Viruses and bacteria infect host cell and there is dynamic interaction between host and the pathogen. While the host mounts responses to prevent infectious agents from propagating, the infectious agent must subvert these responses, invade the host system and establish the infection. The genetics of intricate host-pathogen interaction and the molecular genetics of the infectious agent is the theme of study in the department addressing various deadly diseases including AIDS, tuberculosis, and cancer. The ultimate hope is to develop novel therapeutic and vaccine strategies to combat these diseases.

Areas of investigation include:

  • Genetic analysis of HIV-1 replication focusing on the role of host cellular factors on various steps of HIV-1 replication and antiviral effects of inducing interferon signaling (G. Kalpana)
  • Genetic analysis of tuberculosis including study of drug resistance, development of vaccines, development of bacterial and phage systems to study the genetics of tuberculosis (W. Jacobs)
  • Genetic analysis of transforming retroviruses including the mechanism of induction of tumors by retrovirus-mediated insertional mutagenesis using mouse models (J. Lenz)
infectious-disease-genetics

Human Population Genetics

Understanding the basis of human disease can be best determined by analyzing DNA or RNA from human subjects. This might entail performing genome-wide association studies or screening candidate genes for DNA variations (copy number variation or single nucleotide polymorphisms). After loci are identified, the functional consequences of DNA variations can be understood. Areas that overlap include genetic epidemiology, evolutionary biology and statistical genetics

Areas of investigation include:

human-population-genetics

Neurogenetics

The nervous system and behavior present some of the most complex and urgent unsolved problems in modern biology.  Using diverse genetic approaches, laboratories in the Department of Genetics are addressing questions related to how nerve cells grow and differentiate as well as how they assemble into functional neural pathways and circuits.  Efforts take advantage of several model systems.

Areas of investigation include:

  • Using advanced transgenic methodology to understand how growth factors control specification of mammalian brain regions in developing mouse brain (J. Hebert)
  • Genetic regulatory circuits underlying expression of key genes in mammalian eye development (A. Cvekl)
  • Gene expression in human brain as a function of age (J. Vijg)
  • The role of the extracellular matrix in development and maintenance of neural pathways (H. Buelow)
  • Mechanisms of neural cell fate determination and patterning (N. Baker)
  • Understanding how molecular labels expressed on the surfaces of neurons (neural cell adhesion proteins) code for synaptic connectivity in neural circuits, using the known wiring diagram of the nematode C. elegans nervous system (S. Emmons, J. Secombe)
  • Transcriptional and cellular mechanisms underlying intellectual disability (J. Secombe)
neurogenetics

Stem Cell Genetics

Novel methods of generating differentiated cells from pluripotent cells in vitro has opened new avenues to understand the differentiation process and to obtain cells for pharmaceutical and therapeutic applications. The discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSC) by relatively simple maneuvers has provided the opportunity to derive disease and patient-specific differentiated cells. Members of the Genetics faculty are involved in understanding the molecular mechanisms of the phenotypic transition from somatic to pluripotent cells, as well as from pluripotent to differentiated cells. The information obtained from these projects has great translational potential, because the induced pluripotent stem cells can be expanded in culture, and could serve as a renewable source of autologous differentiated cells for transplantation into patients with various genetic disorders without the need for immunosuppression.

Areas of investigation include:

  • Epigenomic drift in human embryonic stem cells (hESC) during differentiation into neuronal lineages (J. Vijg, A. Maslov)
  • Differentiation of hESC to hepatocytes, including epigenomic profiling during stages of differentiation of hESC and physiological function of the derived hepatocytes (J. Roy-Chowdhury, N. Roy-Chowdhury)
  • Treatment of liver-based genetic disorders (Crigler-Najjar syndrome-1, alpha-1 antitrypsin deficiency and primary hyperoxaluria-1) by reprogramming of somatic cells from patients into iPSC and transplantation of autologous gene-corrected hepatocytes (J. Roy-Chowdhury, N. Roy-Chowdhury)
  • Differentiation of human ES and iPS cells to model human eye development and disease (A. Cvekl)
stem-cell-genetics

Statistical & Computational Genomics

Advances in molecular and computational biology have led to the development of powerful high-throughput methods, allowing quantitative measurements of many types of biological processes. The mission of several faculty members in the Department of Genetics is to apply and develop methods for analyzing and interpreting genetic, genomic, and epigenomic data.  Our focus includes: 1) organization, pre-processing and visualization of raw data, 2) higher-level analyses including integration across diverse genomic platforms, incorporation of clinical data and pathway analysis, and 3) the translation of genomics research into clinically relevant diagnostic tools using statistical models and machine learning algorithms.

Areas of investigation include:

  • Development and application of advanced statistical and computational approaches to analyze genetic and multiomic data, aiming to understand the biological mechanisms underlying human aging and complex diseases, including Alzheimer’s disease, schizophrenia, and congenital heart defects (Z. Zhang).
  • Genome instability and the mechanisms through which this may cause human disease and aging. Computational methods are used for modeling various sources of genome instability and how they give rise to changes in the transcriptome and cell functional decline (J. Vijg)
  • The study of epigenomic dysregulation and how it contributes to common complex human genetic disorders. The technologies required for this research include innovative molecular assays and bioinformatics techniques (J. Greally)
  • Development of computational methods for exploiting patterns in high-throughput genomic data and for integrating information from experimental and computational biology (D. Zheng)
  • Prioritization of candidate loci in epigenome-wide association studies and statistical approaches for incorporating hierarchical genomic structure (M. Fazzari)
statistical-computational-genomics

Transcription

Gene expression is very often regulated, either in response to changes in the environment, or as part of an intrinsic developmental program. Frequently the major regulatory step is transcription of the gene into RNA, and as such, a significant number of Department of Genetics faculty are actively investigating transcriptional regulators. A variety of organisms, including yeast, Drosophila, mouse, and human cell lines are used in the Department, both to investigate cis- and trans-acting regulators of specific genes and also to characterize factors and mechanisms that broadly regulate transcription of the genome.

Areas of investigation include:

  • Mechanistic studies of lineage–specific DNA binding factors that control mouse embryonic development (A. Cvekl, B. Morrow and B. Zhou).
  • Functions of the transcription factor and cell growth regulator c-Myc are being examined in Drosophila (J. Secombe)
  • Regulatory modifications of histones and DNA are studied in flies (J. Secombe), mouse (A. Cvekl, G. Kalpana), human cell lines (J. Greally, G. Kalpana), and yeast (G. Prelich)
  • Chromatin remodeling complexes in cancer (G. Kalpana) and eye development (A. Cvekl)
  • Mechanisms of transcriptional deregulation in aging (J. Secombe, Y. Suh)
transcription