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Molecular and epigenetic regulation of biological clocks

 

K_Padmanabhan

research AREAS

 

 

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. 

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?


Methods:

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).

 
 

ongoing PROJECTS

 

ANR project CHROMAGNON 
With Benjamin AUDIT (Coordinator, Lab Physics, ENS) and JN VOLFF (IGFL, ENS Lyon) 

 

The essential role of chromatin in functional organization of the genome and its expression has been largely ignored in evolutionary studies.

CHROMAGNON -an interdisciplinary and innovative project that bridges evolutionary biology, chromatin structure and mathematical modeling, to understand the function of the sequence-encoded structural organization of chromatin in higher eukaryotes.

 

 

 

                                                     Neuronal micRoscopy for cEll behaVioural Examination and mAnipuLation

     

 

The research groups include physicists and engineers at the CEA Grenoble (Cedric Allier,  project coordinator)  and WUT Poland (Malgorzata Kujawinska), biologists at LMU (Maria Robles) and ENS Lyon (Kiran Padmanabhan) and clinicians at the Policlinico Milano (Luca Valenti).
The SME's include Iprasense (France) and ALS (Germany).

 

 

Our aim is to develop an AI-based neuronal microscope capable of intelligent action

A device with built-in capacity to follow and characterize the behavior of 2-D or 3-D structures in live culture with multiple parameters

A microscope trained to recognize a target based on a data-rich image, its transcriptome and proteome

A device capable of selecting only specific cells of interest from a heterogenous mix for analysis

Revealing heterogeneity inherent in liver dysmetabolism and at the origins of cancers

An AI-powered device that can reveal, predict, act and help discover

 

 

Interested and motivated students, research engineers, postdocs and scientists are encouraged to inquire about positions- 

Areas to be developed in Lyon include scRNAseq analysis during liver dysmetabolism leading to cancer. 

Mouse models and human patient samples (metabolic liver disease to HCC) will be the focus of the analysis. 

We are looking for candidates with skills in hepatobiology, organoid and spheroid development, single cell RNAseq pipeline development and analysis, computational biology.

 

 

Current lab members (Jan 2021):

Lies Chikhaoui (PhD)

Kevin Tartour (Postdoc)

Francesca Andriani (IE)

Marie Fackeure (AI, CDD)

Santiago GONZALEZ (Tech, CNRS)

Damien SERY (Tech, CDD)

Dominika LETKOVA (M2, UCBL)

Elyes Aouadi, Stagiaire EPHE

 

Former trainees/members:

Amandine CAVAROC (AI)

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) 

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)

Helene Boyer (PhD, ENS)

 

 

 

 

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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