Department of Biology
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Overview
In mammalian neurons, synaptic activity-induced alterations in gene expression lead to enduring changes in synaptic transmission and cellular physiology that alter neuronal connectivity. These changes in neuronal connections are important for shaping neuronal circuits during development and for cognitive functions such as learning and memory. We study synaptic activity-dependent regulation of gene expression in cultured neurons from the rodent hippocampus, which is a region of the brain important for long-term memory formation.
Synaptic activity-dependent regulation of gene expression is triggered by the intracellular messengers Ca2+, cAMP and reactive oxygen species. We study the regulation of neuronal transcription factors by these messengers under physiological conditions, during normal brain ageing, and in neurodegenerative conditions.
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In electrically active neurons HDAC4, a transcriptional corepressor protein, translocates to the cytoplasm. |
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A major focus of the current work is to identify how synaptic-activity induced transcriptional changes in neurons influences their interaction with microglial cells and astrocytes. To do this, we are developing novel label-free imaging techniques that allow live imaging of neuronal-microglial interactions. An example can be viewed here http://www.nature.com/article-assets/npg/srep/2016/160226/srep22032/extref/srep22032-s3.mp4.
We are using Drosophila to investigate the role of conserved neuronal transcriptional regulators in learning and memory and in generating rhythmic behaviours such as circadian rhythms of locomotor activity. We have recently identified Class IIa HDACs as conserved regulators of circadian function in both fruit flies and mammalian cells.
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The Class IIa HDAC, HDAC4 is required for robust circadian rhythms of locomotor activity in Drosophila. Double-plotted actograms of wild-type flies (control, left panel), which show robust patterns of daily activity, and HDAC4 hypomorphic flies (HDAC4KG09091, right panel), which are arrhythmic. |
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Research Group
| Name | Status | Project |
|---|---|---|
| Iain Hartnell (MRC funded, with Miles Whittington) |
PhD Student |
Brain rhythms and molecular markers of plasticity (MRC funded, with Miles Whittington). |
| Christopher Ugbode (BBSRC funded, with Sean Sweeney) |
Postdoctoral Research Associate |
Reactive Oxygen Species, metabolic by-products of mitochondrial respiration |
| Jack Munns (funded by a Departmental Studentship, with Seth Davis) | Phd Student | Solving a worm's clock: Conserved transcriptional and non-transcriptional cellular mechanisms |
| Ming Yang | Postdoctoral Research Associate | Intravital multiphoton imaging of the brain: integrating immunology, neuroscience and cancer biology |
Teaching and Scholarship
I am a neuroscientist and teach primarily in this area. I take students through the scientific approaches and landmark studies that have helped unravel fundamental mechanisms and concepts with a view to helping students develop problem-solving skills applicable to any biological field.
I lecture in the Stage 2 Neuroscience module and run the Stage 3 Learning and Memory module. My lecture material aims to help students understand how synaptic transmission is modulated at the cellular level and how this underpins behaviours such as addiction, circadian rhythms and cognition. Evaluating the evidence from scientific studies for established knowledge and concepts is an important feature of my lectures.
My tutorial sessions for Stage 1 students aims to introduce them to ground-breaking work that has dramatically advanced biological understanding. This is done through critical discussions on Nobel prize-winning discoveries where students are free to choose a particular Nobel Prize or Nobel Laureate. For Stage 2 students I run tutorials on Cell Signalling where we consider how fundamental calcium signalling mechanisms are deployed in different cell types to mediate distinct physiological functions.
Undergraduate projects in the lab are aligned to our research interests in the timekeeping mechanisms of cellular circadian clocks. We investigate this in model organisms such as the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans.
Dr Sangeeta Chawla
Lecturer
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Profile
Career
| 2010 - | Lecturer | Department of Biology, University of York |
| 2003 - 2009 | BBSRC David Phillips Fellow | University of Cambridge |
| 2000 - 2003 | Post-Doc | University of Cambridge |
| 1997 - 2000 | Post-Doc | MRC Laboratory of Molecular Biology |
| 1997 | PhD | MRC Laboratory of Molecular Biology |
| 1993 | MPhil | University of Cambridge |
| 1992 | MSc | Jawaharlal Nehru University, India |
| 1990 | BSc (Hons) | University of Delhi, India |
Departmental roles
Disability Liaison Officer
Member: Graduate Studentship Committee
Member: Admissions Team, Biomedical Sciences UCAS
Member: Biomedical Sciences Degree Development Group
Research
Overview
Research in the laboratory is aimed at understanding how neuronal transcription factors respond to growth factors and synaptic activity to direct gene expression programs underlying neuronal differentiation, neuronal growth and synaptic plasticity. We are specifically interested in the regulation of CREB, serum response factor, Elk-1, Class IIa HDACs and the myocyte enhancer factor-2 family of proteins in rodent hippocampal neurons and in differentiating neural progenitors. We are using Drosophila to investigate the role of these transcriptional regulators in learning and memory and in generating rhythmic behaviours such as circadian rhythms of locomotor activity. One aim of our work is to investigate changes in transcription factor regulation in neurodegenerative diseases that are associated with transcriptional dysfunction.
Discoveries
Regulation of histone-modifying proteins: A major contribution of our research is the finding that synaptic activity-induced signalling pathways can regulate transcriptional coactivators and transcriptional corepressors. My early work identified CBP, a histone acetyl transferase, as a target for neuronal signalling pathways -the first report of signal-dependent regulation of a chromatin-modifying enzyme. Since then, other coactivators and corepressors, such as HDACs, have been reported as targets of signalling cascades. We have shown synaptic activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5 in hippocampal neurons. More recently, we have shown that Class IIa histone deacetylases are conserved regulators of circadian function in mammalian cells and in Drosophila.
Differential effects of signalling pathways: We discovered that while MEF2 transcription factors are activated by Ca2+ signalling, cAMP acts to repress MEF2 factors. We have also identified differential effects of calcineurin, a phosphatase that acts to constrain hippocampal synaptic plasticity, on CREB and SRF/Elk1 transcription factors.
Projects
- Reactive Oxygen Species, metabolic by-products of mitochondrial respiration, as
conserved regulators of synapse growth and neuronal homeostasis. (BBSRC funded: Sweeney- PI and Chawla Co-I).
- Intravital multiphoton imaging of the brain: integrating immunology, neuroscience and cancer biology (C2D2 funded: Whittington-PI, Kaye Co-I, Brackenbury Co-I and Chawla Co-I).
Research group(s)
| Status | Name | Project |
|---|---|---|
| PhD Student |
Iain Hartnell (MRC funded, with Miles Whittington) |
Brain rhythms and molecular markers of plasticity (MRC funded, with Miles Whittington). |
| Postdoctoral Research Associate |
Christopher Ugbode (BBSRC funded, with Sean Sweeney) |
Reactive Oxygen Species, metabolic by-products of mitochondrial respiration |
| PhD Student | Jack Munns (funded by a Departmental Studentship, with Seth Davis) | Solving a worm's clock: Conserved transcriptional and non-transcriptional cellular mechanisms |
| Postdoctoral Research Associate | Ming Yang | Intravital multiphoton imaging of the brain: integrating immunology, neuroscience and cancer biology |
Available PhD research projects
Role of redox-signalling and oxidative stress in the regulation of neuronal transcription factors (2016-17)
Synaptic activity-induced changes in neuronal gene expression programs direct neuronal differentiation during development and alter connectivity of adult neurons in response to emotional and sensory stimuli. The Class IIa HDACs, HDAC4 and HDAC5 are transcriptional co-repressors that regulate the activity of the myocyte enhancer factor-2 (MEF2) family of transcription factors. Under basal conditions Class IIa HDACs reside in the nucleus and repress MEF2 transcriptional activity. Derepression of MEF2 factors involves synaptic activity-induced nuclear export of Class IIa HDACs through phosphorylation of two conserved serine residues in their N-termini. Recently, reactive oxygen species (ROS) have been implicated in mediating nuclear export of Class IIa HDACs in muscle through the oxidation of conserved cysteines in HDAC4 and HDAC5. Moreover, HDAC5 displays phosphorylation-independent cyclical changes in subcellular localization (Fogg et al, 2014). This PhD project will examine whether ROS signalling influences HDAC4/5 subcellular localization in primary hippocampal neurons in response to synaptic activity and in response to oxidative stress. It will investigate whether there is an interaction between HDAC4/5 cysteine oxidation and phosphorylation. The project will employ a range of cellular, molecular and biochemical techniques to assess HDAC4/5 localization, phosphorylation and cysteine oxidation in neurons.
References
FoggPCM, O'NeillJS, DobrzyckiT, CalvertS, LordE, LordRL, ElliottCJH, SweeneyST, HastingsMHand Chawla S (2014). Class IIa histone deacetylases are conserved regulators of circadian function. Journal of Biological Chemistry 289, 34341-34348.
