Profile

Career

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)

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.