Heads of Laboratories
Nathaniel Heintz, Ph.D.
Investigator, Howard Hughes Medical Institute
James and Marilyn Simons Professor
Laboratory of Molecular Biology
Research in Dr. Heintz’s laboratory aims to identify the genes, circuits, cells, macromolecular assemblies and individual molecules that contribute to the function and dysfunction of the mammalian brain. Dr. Heintz and his colleagues have developed a suite of novel approaches based on the manipulation of bacterial artificial chromosomes (BACs) to investigate the histological and functional complexities of the mammalian brain in vivo and to understand how these mechanisms become dysfunctional in disease.
Research in the Heintz laboratory focuses on the following four areas.
Genetic dissection of central nervous system (CNS) cell types and circuits. The Heintz laboratory invented DNA engineering by homologous recombination in E. coli (a process now commonly referred to as “recombineering”) and demonstrated that engineered BAC transgenes can be reliably expressed in defined CNS cell types in vivo. Collaborating with Rockefeller’s Mary E. Hatten, the Heintz laboratory launched the NINDS Gene Expression Nervous System Atlas (GENSAT) project (www.gensat.org), a large-scale screen using BAC transgenic mice to create an atlas of CNS gene expression at the cellular level. It provides detailed anatomical data on cell types targeted in over 1,500 BAC transgenic mouse lines and provides a library of verified BAC vectors and transgenic mouse lines. This resource provides a foundation for in-depth analysis of CNS cell types by hundreds of laboratories and provides the genetic tools used by the Heintz laboratory for further investigation of cellular and molecular mechanisms governing nervous system function.
Translational profiling of CNS cell types in health and disease. The Heintz laboratory, in collaboration with Rockefeller’s Paul Greengard, developed the translating ribosome affinity purification (TRAP) technique, which can be used to identify translating mRNAs from genetically targeted cell types. By fusing an affinity tag to a ribosomal protein, TRAP enables the isolation of bound mRNAs from a targeted cell type without requiring isolation of that cell type from the tissue of interest. The laboratory employs bacTRAP transgenic mice and TRAP profiling to determine the molecular constitutions of a wide variety of cell types in the mouse brain and to determine the molecular phenotypes of select cell types in mouse models of autism spectrum disorders, amyotrophic lateral sclerosis, addiction and depression. TRAP profiling has proven to be very powerful in identifying cell types responding to genetic perturbations or pharmacologic interventions, and it has led to the definition of biochemical pathways whose altered activity contributes to the pathophysiology of CNS disorders.
Epigenetic regulation of the neuronal genome: the role of 5-hydroxymethylcytosine (5hmC) in neurons. Over the last several decades, a strong connection between the presence of 5-methylcytosine (5mC), chromatin organization and gene expression has been established. While investigating the relationship between nuclear structure and the content of 5mC in cerebellar Purkinje and granule cell genomic DNA, the Heintz laboratory discovered that 5hmC is present in the mammalian genome and that it is specifically enriched in neurons. Dr. Heintz and his colleagues are now addressing the potential impact of 5hmC, a novel epigenetic mark not previously observed in metazoans, on nuclear structure and gene expression, its significance for epigenetic mechanisms of neurological and psychiatric disease and its role in CNS development.
Biochemical mechanisms of neuronal function. To investigate macromolecular assemblies that govern neuronal function in their native context, the Heintz laboratory has expressed fusion proteins in cell types of interest using BAC transgenic mice, prepared crude fractions that are enriched for the complexes of interest and affinity purified those complexes incorporating proteins of interest. In collaboration with Rockefeller’s Brian T. Chait, the laboratory has identified the protein components of these complex machines by using mass spectroscopy. For example, using this approach, they have characterized the biochemical properties of specific synapse types in the mammalian brain, revealing fundamental biochemical differences between excitatory and inhibitory synapses. Heintz and his collaborators have also characterized large complexes containing Beclin 1, leading to identification of new mechanisms that participate in the regulation of autophagy and endocytosis. These studies demonstrate that in vivo biochemical profiling provides an important avenue toward deciphering the complex phenotypes encountered using conventional genetic perturbations.
Dr. Heintz graduated from Williams College with a B.A. in biology in 1974. He received his Ph.D. from the State University of New York, Albany, in 1979 and then worked as a postdoc at Washington University in St. Louis until 1982. He came to Rockefeller as assistant professor in 1983 and was named associate professor in 1987, professor in 1992 and James and Marilyn Simons Professor in 2006.
Dr. Heintz was granted the American Cancer Society Junior Faculty Research Award in 1986. He was named a Pew Scholar in the Biomedical Sciences in 1985 and received a National Institutes of Health Postdoctoral Fellowship in 1981 and a Damon Runyon-Walter Winchell Cancer Fund Postdoctoral Fellowship in 1979. He is a fellow of the American Academy of Arts and Sciences and an investigator at the Howard Hughes Medical Institute.
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