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Seminars and Conferences

Seminars

Speaker: Dr. Juan Carlos Izpisua Belmonte

Institute: The Salk Institute, The Center of Regenerative Medicine in Barcelona, Spain

Date: Sunday,  June 29


Title: Aging, development and stem cell regeneration


Abstract:

Stem cells are able to generate every other tissue comprising the adult individual. Yet, mammals seem to lack an efficient regenerative response and failure to efficiently regulate tissue homeostasis correlates with the acquisition of aging phenotypes and the appearance of disease. The discovery of reprogramming technologies has shed new light onto the basic mechanism governing cell identity and open new venues for the treatment of human disease.  We will summarize  current advancements and perspectives in regenerative medicine.

 




Speaker: Dr. Yun Xia

Institute: The Salk Institute, The Center of Regenerative Medicine in Barcelona, Spain

Date: Sunday,  June 29



Title: Regenerating kidney in a dish or in-situ?


Abstract:

Chronic kidney disease remains a major burden in human society. Stem cells and reprogramming strategies pose new hopes for the treatment of renal disease. Yet, generation of renal lineages has remained elusive due to the complexity of the kidney, an highly organized 3 dimensional organ in where the interaction of different tissues allow is critical for proper lineage specification and functionality. We will discuss how developmental knowledge can contribute to the establishment of novel paradigms for the generation of renal structures as well as future plans for the induction of a regenerative response for repairing the injured kidney in situ. 

 




Speaker: Dr. Ignacio Sancho-Martine

Institute: The Salk Institute, The Center of Regenerative Medicine in Barcelona, Spain

Date: Sunday, June 29



Title: Reverting development by reprogramming. Are iPSCs the Holy Grail for regenerative medicine?


Abstract:

Reprogramming somatic cell identity to induced pluripotent stem cells (iPSCs) has emerged as a promising approach for the modeling of disease as well as for the directed derivation of specific cell lineages in vivo with the ultimate goal of contributing to alleviating human medical needs. However, reprogramming means far more than generating iPSCs and precise knowledge on the mechanisms underlying this process can bring new light onto the derivation of novel strategies for regenerative medicine the induction of regenerative responses as well as profoundly contribute to our understanding of cancer formation while providing new means for the establishment of novel therapeutics. 





Speaker: Dr. Ali Hamiche

Institute: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Franc

Date: Tuesday, June 24


Title: Epigenetic regulation by histone variants

 

Abstract:

The main research activity of our group is to study the role of histone variants and their deposition machineries in the epigenetic control of human genome activity at the genome-wide level. Among the various epigenetic memory mechanisms, the local replacement of canonical histones within the nucleosome by variant histones has the potential to affect considerably the activity of the corresponding genomic regions. Indeed, nucleosomes bearing histone variants have distinct structures and functional activities in vitro and some histone variants are incorporated at specific genomic locations. Our laboratory is focusing on the role of histone variants in gene regulation and genome integrity. We have implicated macroH2A in PARP-1 enzymatic activity and transcription regulation.  We have identified and characterized the first vertebrate histone chaperone, involved in the deposition of CENP-A at centromeres. We have also investigated in detail the molecular mechanism of the histone variant H3.3 deposition and found that the death-associated protein DAXX and the chromatin-remodeling factor ATRX are crucial components of the H3.3 deposition machinery. Our data argue that DAXX functions as a histone chaperone involved in the replication-independent deposition of H3.3, thus linking apoptosis to gene regulation. Our finding also provides a clue as to how mutations in ATRX gene lead to the human genetic disease of ?-thalassemia and X-linked mental retardation. More recently, we have identified ANP32E as a histone chaperone that removes H2AZ from promoters and provided the molecular basis for H2A.Z recognition and H2A.Z/H2B nucleosomal eviction by ANP32E. We have also identified a novel chaperone involved in H2AZ deposition and discovered a novel new link between the histone variant H2AZ and DNA demethylation. Very recently, we have implicated histone variants in the regulation of circadian clock dynamics. This implication of histone variants in circadian clock regulation is novel and will certainly help us to understand how epigenetic information is stored and transmitted during the cell cycle to daughter cells. Alteration of these epigenetic marks is associated with developmental disorders and cancer.


 




Speaker:Dr. Stefan Dimitrov

InstituteInstitute Albert Bonniot, France

Date: Monday, June 23

 

Title: Chromatin Epigenetics: nucleosome remodeling, histone variants and response to environmental cues

 

 

Abstract:

DNA in the cell nucleus is organized into chromatin. Chromatin impedes the binding of protein factors to the underlying DNA sequences. The cell uses three main “epigenetic tools” to overcome the chromatin barrier, namely:  chromatin remodelers, histone variants and histone post-translational modifications. We will give specific examples of how either one of these “epigenetic tools” function.

 

Chromatin remodelers are sophisticated nano-machines, which are able to alter histone-DNA interactions and to mobilize nucleosomes. Neither the mechanism of their action nor the conformation of the remodeled nucleosomes are, however, yet well understood. We have studied the mechanism of RSC and SWI/SNF-induced chromatin remodeling by using high resolution microscopy and state of the art biochemistry techniques. The data illustrates how RSC remodels the nucleosome in vitro and shed light on its in vivo function.

Histone variants are non-allelic isoforms of conventional histones. CENP-A is a histone H3 variant, which replaces conventional histone H3 at centromeres and is a universal epigenetic centromeric marker. The NH2-terminus of human CENP-A is phosphorylated at serine 7 during mitosis but the role of this phosphorylation remains unknown. We have deciphered the in vivo function of CENP-A NH2-terminus. Our data reveals why the phosphorylation of CENP-A is required for mitosis.

The crystal structure of the CENP-A nucleosome was recently solved. Intriguingly, in contrast to the canonical nucleosome, the CENP-A nucleosome exhibits flexible DNA ends. Why the CENP-A nucleosome exhibits flexible DNA ends is totally unknown. We will present data demonstrating that the more flexible DNA ends of the CENP-A nucleosome are required for its mitotic functions. By using a novel approach, we were able to “rigidify” the ends of the CENP-A nucleosomes in vivo. This results in strong both mitotic and cytokinetic effects associated with the mislocalization of specific protein factors. Our data illustrate how the cell uses the distinct CENP-A nucleosome conformation to control cell division.

 

Recent evidence has demonstrated that histone variants are the key epigenetic actors involved in the response and adaptation at cell and/or at organism level to environmental cues. How this is achieved, remains, however, completely elusive. Our project aims to analyze these questions. We will study the implication of histone variants in cell differentiation and reprogramming, circadian clock function and ageing. These problems will be addressed at both organism and cellular level by using the available in the lab unique conditional knock out mouse lines for a cohort of histone variants, the ES and MEF cells derived from them as well as novel genome-wide based technologies.


 






Speaker: Dr. Wolfgang Fischle

Institute: Max Planck Institute for Biophysical Chemistry, Göttingen, Germany 

Date: May 26, 2014

 

Title: The Biochemistry of Epigenetics: Fundamental Mechanisms of Environmental Adaptation via Readout and Translation of Chromatin Modifications

Abstract:

To sustain life in different environments cells and organisms must adjust to different conditions and external cues. In contrast to immediate and mostly transient responses to short-term stimuli, processes of long-term adaptation require lasting changes in gene expression patterns. Such epigenetic changes are controlled on the level of chromatin, the packaging form of eukaryotic genomes. Here, different DNA and histone modifications are associated with distinct functional states of chromatin.

Overall, my research aims to gain detailed, fundamental understanding of the processes that read and translate patterns of chromatin marks for mediating biological outcomes. Currently, we are interested in two main questions. A) How do histone modifications in conjunction with DNA methylation establish seemingly stable chromatin structures in response to internal and external cues? B) How do small cellular metabolites and signaling molecules tune the readout of chromatin marks in processes of environmental adaptation? To address these problems we are using highly interdisciplinary approaches. We are aiming at advancing technologies for establishing and analyzing complex chromatin systems in vitro (biochemistry and biophysics), we are applying molecular and cellular biology for studying the interplay of chromatin components with the environment and we have set up systems for systematic and global analysis of modules of epigenetic regulation. 

Our work addresses basic problems of chromatin regulation. I believe these are required for developing theoretical concepts as well as for setting up practical approaches for interference with epigenetic pathways to the benefit of mankind in health and disease.

 





Spea

ker: Dr. Germano Cecere

Institute: University La Sapienza, Italy

Date: May 21, 2014

 

Title: Insect factory: Recombinant protein production using silkworm-baculovirus expression system

 

Abstract:

RNA interference (RNAi) is largely known as a negative regulator of gene expression. The mechanisms by which RNAi negatively regulate gene expression include Argonaute proteins and their small RNA cofactors short interfering RNAs (siRNAs) inhibiting mRNA translation, mRNA or pre-mRNA degradation, and RNA transcription. Interestingly, the association of nuclear Argonaute proteins with transcriptionally active gene loci has been described in animals, including human, raising the interesting possibility that RNAi-mediated mechanism could regulate active genes. 

I will present the results of my work on the C. elegans nuclear Argonaute protein CSR-1. CSR-1 binds endogenous siRNAs (endo-siRNAs) that are antisense to thousands of active germline transcripts. CSR-1 associates with chromatin, and inactivation of the components of the CSR-1 pathway leads to sterility, embryonic lethality, and chromosome organization defects. To investigate the nuclear role of CSR-1, I used the most advanced quantitative genomic methods for studying Pol II transcription, the Global Run-On sequencing (GRO-seq), which I adapted for use in C. elegans. Surprisingly, I discovered that CSR-1 and its associated endo-siRNAs globally promote sense-oriented Pol II transcription of germline genes. Moreover, CSR-1 directly interacts with nascent RNA target transcripts and the Pol II machinery in siRNA-dependent manner. Loss of CSR-1 function results in global increase in antisense transcription and ectopic transcription of silent chromatin domains, which affects centromere formation and chromatin organization. Together, these results suggest that the CSR-1 pathway has a role in maintaining the genome-wide distribution of Pol II and thus propagating the distinction between active and silent chromatin domains. I propose a model where CSR-1 endo-siRNAs may constitute an RNA-based system for propagating the memory of actively transcribed genomic chromatin regions.

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