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Malik, Athar

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Malik

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Athar

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Malik, Athar

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2012 - 20133

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Author's Publications: search.filters.isAuthorOfPublication.9ce26c5e-5fe3-43d8-927d-d73e560ee95b

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    A Chemical Genetic Approach Reveals Distinct Mechanisms of EphB Signaling During Brain Development
    (2012) Soskis, Michael J.; Ho, Hsin-Yi Henry; Bloodgood, Brenda L.; Robichaux, Michael A.; Malik, Athar; Ataman, Bulent; Rubin, Alex A.; Zieg, Janine; Zhang, Chao; Shokat, Kevan M.; Sharma, Nikhil; Cowan, Christopher W.; Greenberg, Michael
    EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, as EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knockin mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly, and specifically blocked. Using these mice we demonstrate that the tyrosine kinase activity of EphBs is required for axon guidance in vivo. By contrast, EphB-mediated synaptogenesis occurs normally when the kinase activity of EphBs is inhibited suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, these experiments reveal that EphBs control axon guidance and synaptogenesis by distinct mechanisms, and provide a new mouse model for dissecting EphB function in development and disease.
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    Genome-Wide Identification and Characterization of Stimulus-Responsive Enhancers in the Nervous System
    (2013-08-21) Malik, Athar; Greenberg, Michael Eldon; Clapham, David; Walsh, Christopher; Bernstein, Bradley; Young, Richard
    During development, intrinsic genetic programs give rise to distinct cellular lineages through the establishment of cell type specific chromatin states. These distinct chromatin states instruct gene expression primarily through the genome-wide demarcation of enhancers. In addition to maintaining cellular identity, the chromatin state of a cell provides a platform for transcriptional responses to environmental signals. However, relatively little is known about the influence of extracellular stimuli on chromatin state at enhancers, and it is not clear which enhancers among the tens of thousands that have been recently identified function to drive stimulus-responsive transcription. In the nervous system, the chromatin state of terminally differentiated neurons not only maintains neuronal identity but also provides a platform for sensory experience-dependent gene expression, which plays a critical role in the development and refinement of neural circuits and in long-lasting changes in neuronal function that underlie learning, memory, and behavior. Using chromatin-immunoprecipitation followed by high through put sequencing (ChIP-Seq), we determined the effects of neuronal stimuli on the active chromatin landscape of mouse cortical neurons. We discover that stimulation with neuronal activity and brain derived neurotrophic factor (BDNF) cause rapid, widespread, and distinct changes in the acetylation of histone H3 lysine 27 (H3K27Ac) at thousands of enhancers throughout the neuronal genome. We find that functional stimulus-responsive enhancers can be identified by stimulus- inducible H3K27Ac, and we use this dynamic chromatin signature to discover neuronal enhancers that respond to neuronal activity, BDNF, or both stimuli. Finally, we investigate the transcriptional mechanisms underlying the function of stimulus responsive enhancers. We show that a subset of stimulus-responsive enhancers in the nervous system require the coordinated action of the stimulus-general transcription factor activator protein 1 (AP1) with additional stimulus-specific factors. Our studies reveal the genome-wide basis for transcriptional specificity in response to distinct neuronal stimuli. Furthermore, the comprehensive identification of neuronal activity and BDNF-dependent enhancers in cortical neurons provides a critical resource for elucidating the role of stimulus-responsive transcription in synaptic plasticity, learning and memory, behavior, and disease. Finally, the epigenetic signature of stimulus-inducible H3K27Ac may aid in the identification and study of stimulus- regulated enhancers in other tissues.
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    CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development
    (2013) Mochida, Ganeshwaran; Ganesh, Vijay; de Michelena, Maria I.; Dias, Hugo; Atabay, Kutay D.; Kathrein, Katie L.; Huang, Emily; Hill, Robert; Felie, Jillian M.; Rakiec, Daniel; Gleason, Danielle; Hill, Anthony D.; Malik, Athar; Barry, Brenda J.; Partlow, Jennifer; Tan, Wen-Hann; Glader, Laurie; Barkovich, A. James; Dobyns, William B.; Zon, Leonard; Walsh, Christopher