Engineered histone acetylation using DNA-binding domains (DBD), chemical inducers of dimerization (CID), and histone acetyltransferases (HAT) BCBP Research Proposal Feynman Liang Amherst College fl[email protected]5/2/2014 Feynman Liang (AC) DBDs, CIDs, and HATs 5/2/2014 1 / 14
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Engineered histone acetylation using DNA-binding domains (DBD), chemical inducers of dimerization (CID), and histone acetyltransferases (HAT) BCBP Research Proposal
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Engineered histone acetylation using DNA-bindingdomains (DBD), chemical inducers of dimerization
(CID), and histone acetyltransferases (HAT)BCBP Research Proposal
Optimize dimerization ligand’s lipophilicity and bioorthogonality(e.g.g bump-hole)
Use another TF that binds the canonical E-box (e.g. USF [9]) as DBD
Try other HATs
Bromodomain ligand for CID conjugate partner
Recruit endogeneous HAT“. . . not inhibit any enzymatic function in the recruited [HAT] andwould even be predicted to recruit complexes in a natural orientation”[12]Bromodomain inhibitor already discovered [13]
Circadian regulator CLOCK is a histone acetyltranferase.Cell 125(3), 497–508 (2006)
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A molecular mechanism for circadian clock negative feedbackScience 332(6036) (2011)
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Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and DeacetylationMol Cell Bio, 24(14), 6278–6287, (2004)
Rodd et al.
Current and Emerging Therapeutics for Cutaneous T-Cell Lymphoma: Histone Deacetylase InhibitorsLymphoma 2012(290685), (2012)
Wang et al.
Intermolecular recognition revealed by the complex structure of human CLOCK-BMAL1 basic helix-loop-helix domainswith E-box DNACell Research, 23:213–224, (2012)