PROJECTS

 

The Bosco lab has two major interests:  1. Chromosome, chromatin dynamics and gene regulation.  2. Learning, memory, aging and mechanisms of trans-generational inheritance.

Chromosomes:

Condensins and Chromosome Compaction

We are interested in understanding the molecular basis of how nuclear architecture, chromosome and chromatin structure and how changes in these structures impact gene expression. We are also interested in how changes in structure influence genetic and epigenetic inheritance of physical traits.  We use the fruit fly, Drosophila melanogaster, and human tissue culture cells as our model systems. Currently, we are focusing on the tiny molecular machines that work on DNA, called condensins, that regulate the topological conformation of DNA molecules within the cell. Condensins modulate a variety of dynamic DNA structures that in turn render DNA sequences more or less accessible to protein and/or small RNA molecules that regulate gene expression. Our previous work has shown that condensins can alter how chromosomes physically interact with one another, and that these interactions are critical for proper regulation of gene expression, heterochromatin and epigenetic gene silencing, meiotic chromosome segregation and global chromosome organization within the nucleus. More recently, we have focused on condensin interacting proteins that recruit these molecular machines to specific histone modifications within the genome, such as actively transcribed regions and satellite repeats within heterochromatin.  This project has been funded by NIH NIGMS and has been a fun collaboration with the lab of Greg Rogers at the University of Arizona. For more details, click on our publications tab at the top of this page.  Scroll down to see full list of collaborators and links to their lab websites.

3D Genome and Condensins

We have active collaborations with computational groups at Dartmouth (Casey Greene and Chao Cheng) and chromatin biology labs at Emory (Victor Corces)  and Harvard (Chao-Ting Wu) where we seek to model the dynamic processes of genome organization within 3-dimensional space. By using computational, genetic and genomic methods we hope to elucidate how condensin mediated gene spatial localization impacts gene expression and inheritance. We now know that condensins regulate the expression of large numbers of genes, and in particular how their transcription changes in response to stress-induced alterations in 3D-genome organization. Scroll down to see full list of collaborators and links to their lab websites.

Transvection, Chromosome Pairing & Chromosome Territories

            This project was initially inspired by the work of Ed Lewis who first showed that different mutant alleles of the Drosophila Ubx gene interact and result in wild-type function. We now know that Lewis' observations were due to transcriptional activation of the promoter on one allele by the enhancer of the other allele. Lewis called this transvection. Now it is accepted that 3-dimensional chromosome organization is important for gene regulation, such as the trans-interactions Lewis proposed. However, the molecular forces that establish and maintain specific 3D organizational states remain enigmatic. We have begun to unravel the mystery of how pairing and transvection works:  (1) Our seminal work showed that homology dependent pairing of somatic chromosomes and transvection is actively regulated by chromatin condensation. Compaction state determines the degree to which homologous chromosomes can interact with one another at the global and local level, and this condensation state is regulated by condensin II activity (Hartl, et al., 2008. Science, Nov 28;322(5906):1384-7.)  (2) We have shown that condensin function is a general regulator of homolog interactions in diploid somatic tissues, polyploid-polytene somatic and germline tissues, as well as germline cells undergoing meiosis (Hartl et al., 2008 PLoS Genetics Oct;4(10):e1000228; Hartl, et al., 2008. Science, Nov 28;322(5906):1384-7).  (3) Our work has produced the first molecular model of how chromosome territories are established and maintained. We have shown that interphase compaction forces compress chromatin into self-assembling compartments by using chromatin tethers to the nuclear envelope (Bauer et al., 2012 PLoS Genetics 8(8): e1002873). We believe that the mechanisms that regulate chromosome processes in Drosophila will teach us very important lessons about the most basic and universal principles of how DNA and chromatin function in all organisms, including human cells.

 

Condensins and Aging

The Bosco lab is also interested in understanding basic mechanisms of chromosome and nuclear architecture that may be important for aging biology. There are numerous human diseases and pathologies (for example cancer, progeria, muscular dystrophy and others) that are either associated with or caused by mutations in nuclear and chromosomal structural proteins. We seek to understand how nuclear lamin and nuclear pore complex proteins cooperate with condensins to maintain 3-dimensional spatial organization of genomes, and how loss of specific spatial organizational states contributes to human disease and normal human aging. In this project we use both Drosophila and human cells as our model systems. This project has been funded by a generous grant from the American Foundation for Aging Research (AFAR) since 2013.

 

 

Learning, memory and aging:

The L100 Project

            The average human lifespan is being extended such that an ever increasing number of Americans are living to 100 years old and beyond. Consequently, as life expectancy of humans continues to increase, the occurrence of cognitive deficits and memory loss is also on the rise. A significant barrier to addressing this increase in cognitive deficits and memory loss is our lack of understanding of the molecular basis of long-term memory maintenance and its age-dependent loss. Thus, molecular genetic insights into the mechanisms of memory loss will have broad and potentially profound implications for the prevention, treatment and reversal of age-dependent memory loss in humans. To address this grand challenge we have formed an interdisciplinary group of five Dartmouth labs. We use the Drosophila model developed in the Bosco lab for discovery of genetic factors regulating maintenance of long-term memory. The fast ten-day generation time and relatively inexpensive Drosophila system will allow high-throughput screening. The genetic "hits" revealed by the Drosophila screens will then be tested using cell biological and electrophysiological approaches currently employed in the Bosco, Luikart and Maue labs. Furthermore, the Henderson, Bucci, Maue and Luikart labs will extend experiments in Drosophila to test the roles of candidate genes through molecular, electrophysiological and behavioral assays in mammalian systems. In turn, new molecular models developed in these mammalian systems will close the loop and inform further experiments and screens in the Drosophila system. We have formed a synergistic group with the primary goal of elucidating the molecular mechanisms of age-dependent decline of memory and cognitive functions by using a variety of vertebrate and invertebrate experimental systems already in place. We will employ our complementary expertise and technologies to co-mentor students and post-doctoral fellows and guide novel projects. This project was launched in July 2014 with a generous seed grant from the office of the Provost at Dartmouth College. Scroll down to see full list of collaborators and links to their lab websites.

Flies and Social Learning

            This project started off as a crazy idea:  We asked "do flies talk to one another?  If so, what are they talking about?"  We affectionately refer to this as the "talking fly project."  This project seeks to understand the neurobiology of how social animals communicate with each other, learn about their environment, and in turn how this social learning is consolidated into memory that alters behavior for several days-- long after the initial environmental cues have vanished.  Although Drosophila fruit flies are typically not known as social insects (like honey bees for example) we and others have found that they do display an extraordinary ability to communicate with one another. For example, individual or groups of flies that sense the presence of predators that prey on fly larvae trigger physiological changes in their ovaries that slows down egg production.  This deprives the predator their prey.  Amazingly, flies remember their encounter with predators and egg-laying depression persists for several days. What is even more astounding is that predator exposed flies can "teach" naïve flies that have never seen predators to trigger the same physiological changes and depress their egg-laying. We have discovered that predator-exposed flies communicate predator stress by flicking both their wings in precise movements that somehow communicate a "danger signal" to their naïve friends. We are now interested in understanding the neurogenetic components that control this behavior as well as the anatomical parts of the fly brain that may be specifically contributing to social learning and communication. So, does this have anything to do with human health?  We think it does! We know that genes that are typically mutated in human forms of autism and intellectual disabilities in children (for example FMRP and PTEN) are absolutely required for this social communication and learning in the fruit fly. So, in addition to this being an inherently interesting biology question, we think that this project is highly relevant to development of human brain functions as it pertains to social cognitive functions. This new and exciting project has been a collaboration with Mani Ramaswami who is a prominent neuroscientist running labs at Trinity College, Dublin, Ireland and NCBS, Bangalore, India. Scroll down to see full list of collaborators and links to their lab websites.

Trans-generational Behavior and Memory

           This project is really crazy and highly speculative:  We asked "Can the social experiences of parents be inherited by their offspring?" One of the most exciting findings of modern molecular genetics has been that the information encoded in our DNA cannot completely explain heritability of complex traits. This "missing heritability" is now being intensely studied in every living system. At the same time we are now rediscovering how a mind-body connection through which cognitive experiences can have profound effects on physiology and health. However, the possibility that cognitive experiences, or state-of-mind, can contribute to heritability is relatively unexplored at the level of molecular genetics. In social animals, groups of individuals share information about the environment and about themselves, and these social interactions also can result in dramatic physiological changes. Interestingly, because the physiological consequences of social interactions can be long-lasting it raises the exciting possibility that socially learned behaviors affecting the mind become epigenetically embedded and could result in trans-generational effects. How social experiences epigenetically reprogram germline cells in order to transmit information to subsequent generations is terra incognita.

            Social behavior is the ability to transmit and receive information about oneself and the environment in the context of groups of individuals that share this information. The ability to learn about important changes in the environment from others' experiences presents a huge advantage. In this project, we pose two questions: First, what are the specific cellular and molecular mechanisms that underlie the "mind-body" connection making it possible for a cognitive social experience affecting the mind to alter germline cells of the body?  Second, can this altered germline information lead to inherited behavior? If such trans-generational inheritance of behaviors exist, and we argue they do, then we must understand them at the molecular level. Indeed, reports in the literature suggest that parental experiences can influence the behavior of their offspring. We aim to provide compelling evidence from our own work that establishes a completely new experimental paradigm for studying physiological effects of social learning on germline cells. Using this novel system as a tool, we will test whether the observed physiological changes in germline cells also confers inheritance of specific behaviors. Imagine:  Next time you make a decision about something ask yourself "is that really me choosing OR is that some behavioral predisposition I inherited from my parents' social experiences?" This project is not funded as of 01/2015, but it's sooo cool that we're just waiting for NIH or some other generous donor to support it.

 


Collaborators

Mani Ramaswami, Trinity College Dublin, Ireland and NCBS, Bangalore, India

http://www.gen.tcd.ie/ramaswami/index.php

Gregory Rogers, University of Arizona, Tucson, AZ.

http://rogerslab.arizona.edu/

Chao-Ting Wu, Harvard Medical School

http://transvection.org/

Victor Corces, Emory University, Atlanta, GA.

http://www.biology.emory.edu/research/Corces/labmainext.html

Casey Greene, Dartmouth, Hanover, NH.

http://www.greenelab.com/

Chao Cheng, Dartmouth, Hanover, NH.

http://www.dartmouth.edu/~chaocheng/people.html

David Bucci, Dartmouth, Hanover, NH.

http://sites.dartmouth.edu/buccilab/

Bryan Luikart, Dartmouth, Hanover, NH.

http://www.synapticplasticity.com/

Leslie Henderson, Dartmouth, Hanover, NH.

http://geiselmed.dartmouth.edu/henderson/

Robert Maue, Dartmouth, Hanover, NH.

https://geiselmed.dartmouth.edu/faculty/facultydb/view.php?uid=101