Current and recent members of the Van Vactor and Perrimon laboratories at HMS have created a transgenic resource to allow conditional analysis of in vivo functions for over 140 microRNA genes in Drosophila with spatial and temporal precision. This resource, just published in Nature Communications, represents a highly collaborative project that will open the door to a broad variety of novel functional screens. Using this toolkit to explore the landscape of regulatory function in muscle tissue, they discovered a dozen microRNAs required for the maintenance of flight muscle form and function, suggesting that post-transcriptional mechanisms may be vital for protecting muscle from degeneration.
Using a combination of live cell imaging and single cell genome sequencing (Look-Seq), the Pellman laboratory has defined a mechanism for a new mutational process in cancer and congenital disease called chromothripsis (Zhang et al., Nature, 2015). In chromothripsis there is massive rearrangement of typically one of a cell’s chromosomes, leaving the rest of the genome unaltered. By recreating chromothripsis in the laboratory, the group shows that it can originate from abnormal nuclear structures, common in cancer cells, called micronuclei. The findings illustrate the importance of nuclear architecture and integrity for the maintenance of genome stability. The work was done in collaboration with Matthew Meyerson’s laboratory (Dana-Farber Cancer Institute & Department of Pathology at Harvard Medical School).
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Alternative splicing (AS) contributes to the proteomic diversity. In the brain, it emerges as a pervasive mechanism that plays a crucial role in the regulation of neuron maturation and activity. Chromatin modifying enzymes, that impact chromatin structure and globally control specific gene expression programs, are also subject to AS. However, at molecular level, it is poorly understood how AS can affect enzyme substrate specificity. In a recent publication in Molecular Cell (Laurent B. et al., PMID 25684206), Shi lab shed light on how AS can switch the enzymatic activity of the histone demethylase LSD1. In neurons, AS generates LSD1+8a, a LSD1 isoform containing an additional exon of 4 amino-acids (E8a). LSD1 has been reported to repress gene expression by demethylating histone H3K4. In their study, the authors show that the LSD1+8a isoform does not have the intrinsic capability to demethylate H3K4. Instead, LSD1+8a mediates H3K9 demethylation, in collaboration with the SVIL protein, and activate gene expression at its target promoters. Moreover, LSD1+8a and SVIL knockdowns increase H3K9 methylation levels at their target genes and compromise neuronal differentiation. These findings highlight AS as a means by which LSD1 acquires selective substrate specificities (H3K9 vs H3K4) to differentially control specific gene expression programs in neurons.
Note: This Shi lab publication was commented in its related Molecular Cell issue (Shin J. et al., PMID 25794611).
Breathing is essential for survival, and under precise neural control. The vagus nerve is a major connection between lung and brain required for normal respiration. In a recent publication in Cell, the Liberles Lab used molecular and genetic approaches to deconstruct the sensory vagus nerve, identifying two small populations of sensory neurons that exert powerful and opposing effects on breathing. Genetically guided anatomical mapping using Cre/LoxP technology revealed that these neurons densely innervate the lung and send long-range projections to different stereotyped brainstem targets. Optogenetic stimulation of one neuron type (P2ry1) acutely silences respiration, trapping animals in a state of exhalation, while activating another (Npy2r) causes rapid and shallow breathing. Activating P2ry1 neurons had no effect on heart rate and gastric pressure, other essential vagus nerve functions. Thus, the vagus nerve contains genetically definable labeled lines with different anatomical connections and autonomic roles. Specific manipulation of breathing-control neurons electrically or pharmacologically may impact airway diseases like asthma or apnea.
Congratulations to Tobi Walter, who was chosen from a group of 894 eligible applicants to be one of 26 newly-minted Howard Hughes Medical Institute (HHMI) Investigators! HHMI investigators will receive the flexible support necessary to move their research in creative new directions. The initiative represents an investment in basic biomedical research of $153 million over the next five years.
The scientists represent 19 institutions from across the United States. The new HHMI investigators – which include three current HHMI early career scientists -- were selected for their individual scientific excellence.
HHMI will provide each investigator with his or her full salary, benefits, and a research budget over their initial five-year appointment. The Institute will also cover other expenses, including research space and the purchase of critical equipment. Their appointment may be renewed for additional five-year terms, each contingent on a successful scientific review.
HHMI encourages its investigators to push their research fields into new areas of inquiry. By employing scientists as HHMI investigators — rather than awarding them research grants — the Institute is guided by the principle of “people, not projects.” HHMI investigators have the freedom to explore and, if necessary, to change direction in their research. Moreover, they have support to follow their ideas through to fruition — even if that process takes many years.
The National Academy of Sciences recently announced the election of 84 new members and 21 foreign associates from 15 countries in recognition of their distinguished and continuing achievements in original research. Among this list is Fred Goldberg, Professor of Cell Biology. The National Academy of Sciences is a private, non-profit society of distinguished scholars. Established by an Act of Congress, signed by President Abraham Lincoln in 1863, the NAS is charged with providing independent, objective advice to the nation on matters related to science and technology. Scientists are elected by their peers to membership in the NAS for outstanding contributions to research. Congrats Fred!
The American Diabetes Association will present the Outstanding Scientific Achievement Award to Pere Puigserver, PhD. Supported by an unrestricted educational grant from Lilly USA, LLC, this prestigious award recognizes research in diabetes that demonstrates particular independence of thought and originality. Dr. Puigserver will be recognized with this honor at the Association’s 75th Scientific Sessions, taking place June 5-9, 2015, at the Boston Convention and Exhibition Center in Boston. Congrats Pere! For more information, click here.
Peter Cobb, an HMS IT Client Service Representative who supports Cell Biology, was recently named a "Harvard Hero." This Harvard University-wide employee recognition program is designed to recognize “above and beyond” achievement among Harvard’s high-performing staff and their many contributions to the University. Only 64 individuals from over 12,000 Harvard staff were selected as Harvard Heroes in 2015! Congrats to Peter!
On Thursday, April 23, 2015, Bruce Spiegelman, PhD, was awarded the 2015 InBev-Baillet Latour Health Prize, in recognition of his outstanding contributions to the field of metabolic disorders. Dr. Spiegelman received this award at the "Palais des Académies," in the presence of H.M. Queen Mathilde of Belgium. Congratulations to Bruce on receiving this prestigious honor!
Organisms across the evolutionary spectrum have evolved mechanisms to maintain the integrity of the cellular proteome. Among these mechanisms are spatial protein quality control pathways in which damaged and misfolded cellular proteins are actively sequestered at unique subcellular structures in response to acute stress. This mitigates the deleterious effects of these aberrant protein species, which can include advanced cellular aging and cytotoxicity leading to cell death. Despite the universal importance of such spatial control of the proteome, there is considerable mechanistic diversity throughout the evolutionary scale regarding how this control is achieved. In a recent publication in Cell Reports (Egan and McClintock et al., PMID 25865884) the Reck-Peterson Lab expanded on the known evolutionary diversity of spatial quality control mechanisms by examining the subcellular organization of heat-induced protein aggregates in filamentous fungi, which are of substantial health and economic importance and serve as a model for transport processes in other polarized eukaryotic cells. Using Aspergillus nidulans, the Reck-Peterson group found that protein aggregates are actively organized at periodic subcellular structures in a process dependent on microtubules and their associated motor dynein. In addition, they found that sustained stress and increased burdening of this spatial quality control pathway can lead to defects in other microtubule-based transport processes. Given the significance of protein aggregation and polarized transport in neurodegenerative disorders, as well as the pathogenicity of many filamentous fungi, this work suggests several avenues of further investigation for understanding and combating disease.