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Molecular and epigenetic regulation of biological clocks

 

K_Padmanabhan

Presentation of research topics developed by the team of Kiran Padmanabhan (in English).

Our lab studies molecular and epigenetic pathways that control biological oscillators, especially those that help establish and operate mammalian circadian clocks. In general, we use the circadian clock as an archetype to study the epigenetic organization and regulation of the genome. In particular, we are interested in understanding how specific chromatin environments – or epigenetic states – determine recognition by BMAL1:CLOCK::PER:CRY (the core-clock proteins) of its binding sites in the human and mouse genomes, and how the core-clock complexes modify chromatin to regulate gene expression. Our research while exploring the activity of the core-clock protein complex and its action on the genome could inform us about the role of the clock on cell cycle progression, its impact on tumor development and aging.

Of the many epigenetic regulators, we are particularly interested in histone variants – key factors that control transcriptional outputs by regulating chromatin structure. With this in mind, we are interested in understanding:

i)      the molecular principles that drive 24hr variant chromatin states.

ii)     how variant chromatin structure impacts 24 hour rhythms in clock protein complex assembly, disassembly and
        propagation on DNA.

iii)    how are these phenomena modulated during normal and pathological aging? What are the immediate, intermediate and 
        long-term impacts of circadian desynchrony on the cellular genome  and chromatin and are they reversible?

We are taking an integrative approach to tackle the problem at hand. 
 
We use proteomics and next-generation sequencing to characterize variants and clock complex dynamics on chromatin along with transcriptomes. We do this on animals raised under normal environmental conditions or from cohorts subject to various systemic stressors that alter circadian clock function and the regulation of chromatin state. In addition, we carry out real-time imaging studies on live circadian reporter mouse models, isolated cells and neurons (wildtype or conditionally deleted for histone variants).

 

 
 

Figure 1: Circadian expression of the Rev-Luc transgene in mice by bioluminescence imaging. Left, representative luminescent imaging of the same anesthetized Rev-Luc reporter transgenic mice over time for the ventral and dorsal faces. Right, quantitative bioluminescence radiance as a function of zeitgeber time for ventral (n=34) and dorsal (n=15) expositions. The fitted dark line represents the mean cosine wave of best fit with a 24 h period. (Canaple et al, Unpublished)

Figure 1. Circadian expression of the Rev-Luc transgene in mice by bioluminescence imaging. Left, representative luminescent imaging of the same anesthetized Rev-Luc reporter transgenic mice over time for the ventral and dorsal faces (kind gift from L. Canaple and J.Samarut).

Right, quantitative bioluminescence radiance as a function of zeitgeber time for ventral (n=34) and dorsal (n=15) expositions. The fitted dark line represents the mean cosine wave of best fit with a 24 h period. (from Canaple L et al, Cell Mol Lif Sci 2018).

Figure 2: Real-time bioluminescence from mouse fibroblasts expressing a Bmal1-Luc reporter.

 

 

 

Interested and motivated students or postdocs or scientists are encouraged to inquire about positions- 

 

Current lab members:

Helene Boyer (PhD, ENS)

Lies Chikhaoui (PhD)

PhD co-supervisor : Lorrie Ramos (UGA, Grenoble)

Kevin Tartour (Postdoc)

Francesca Andriani (IE)

Olivia Bartle (M1, ENS Biosciences)

Victor Malassigne ( Intern)

Celia Tourlonias (Intern- co trainee with Merabet lab)

Former trainees/members:

Pauline Abrial (AI)

Anuvind KG (M2, IISER Pune)

Jerome Poizat (3rd year, ESTBB Lyon)

Gonzalo Hernandez (M1, Univ Rennes)

Eric Folco (Postdoc)

Jugal Mohapatra (Summer Intern- IIT Kharagpur)

Yann Sakref (L3, ENS Lyon)

Sarah Heintz (Stagiare, 2nd yr, ESTBB)

Shannin Arenales Castillo (Masters student year 1), ENS Biosciences

Isahak Saidi (Masters student, year 2) ; currently at Champalimaud Neuroscience Programme.

Lies Chikhaoui (M1 student, Univ Lyon)

Nicolas McAdams (M2 student, Univ Lyon)

Laurence Canaple (IR2, CNRS)

Aysegul Ors (PhD, Grenoble and Bilkent University)

Stella Chausheva (currently- PhD student, Medical University of Vienna)

 

 

 

Key References:

1. Padmanabhan K#.  and Billaud M. Desynchronization of Circadian clocks in Cancer : A metabolic and epigenetic connection. Front
    Endocrinol
,  8 :136. 2017.

2. Ors A, Papin C, Favier B, Roulland Y, Dalkara D, Ozturk M, Hamiche A, Dimitrov S and Padmanabhan K#. Histone H3.3 regulates
    mitotic progression in mouse embryonic fibroblasts. Biochemistry and Cell Biology, 2017, doi: 10.1139/bcb-2016-019.
 

      http://www.nrcresearchpress.com/eprint/MVAZKjrbrGY2e2Ji7ns7/full

3. Roulland Y , Ouararhni K , Naidenov M , Ramos L , Shuaib M , Syed SH , Lone IN, Boopathi R, Fontaine E , Papai G ,Tachiwana H,
    Gautier T , Skoufias D , Padmanabhan K , Bednar J , Kurumizaka H,  Schultz P, Angelov D , Hamiche A & Dimitrov S. The flexible
    ends of CENP-A nucleosome are required for mitotic fidelity. Molecular Cell. 32081-7(16).  2016

4. Obri A, Ouararhni K, Papin C, Diebold ML, Padmanabhan K, Marek M, Stoll I, Roy L, Reilly PT, Mak TW, Dimitrov S, Romier C and
    Hamiche A. ANP32E is a histone chaperone that removes H2A.Z from chromatin. Nature. 505: 648-53. 2014

5. Padmanabhan K, Robles M, Westerling T and Weitz CJ. Feedback regulation of transcriptional termination by the mammalian   
    circadian clock PERIOD complex. Science. 337: 599-602. 2012


6. Robles M, Boyault C, Knutti D, Padmanabhan K and Weitz CJ. Identification of RACK1 and protein kinase Calpha as integral      
    components of the mammalian circadian clock. Science. 327: 463-6, 2010.

The lab's research benefits from funding from:


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