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%Page de titre:
\title[]{\emoji{dna} Genetic alterations in ChIP-seq}

\author{Dr. Thomas Steimlé}

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\date{\today}


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\begin{document}

\begin{frame}
\maketitle
\thispagestyle{empty}

\end{frame}


\begin{frame}{\emoji{drop-of-blood} Background --- Thymopoiesis}
  \begin{itemize}
    \item<1-> During thymopoiesis (HSC $\Rightarrow$ T-cell), the phenotypic diversity of 
    the antigen receptor (TCR) is acquired.
  \end{itemize}
  \centering
    \includegraphics<1>[width=.4\textwidth]{Images/dev_thym.png}
    \includegraphics<2>[width=.6\textwidth]{Images/Tcr_str.png}
\end{frame}

\begin{frame}{\emoji{drop-of-blood} Background --- V(D)J recombination}
  \begin{itemize}
    \item<1-> This process involves a series of genome recombination of the different TCR loci 
    followed by \alert{proliferation selection of functionnal non self-reacting receptors}.
  \end{itemize}
  \centering
    \includegraphics<1>[width=.7\textwidth]{Images/MaturLt.png}
    \includegraphics<2>[width=.7\textwidth]{Images/TCRBschema.jpg}
\end{frame}

\begin{frame}{\emoji{dna} Background --- V(D)J recombination}
  \begin{columns}
    \begin{column}{.5\textwidth}
      \begin{itemize}
        \item V(D)J recombination is a \alert{threat to genomic stability}, 
        prone to induce \alert{DSB occurring in genes outside of the TCR loci}, 
        followed by erroneous repair resultating in SV.
        \item This oncogenesis process is responsible of well known genetic alterations 
        in T-ALL (particulary translocations accountable of ectopic expression of oncogenes 
        \textit{TLX1}, \textit{TAL1} etc\dots)$^1$.

        \footnotetext{
          \tiny
          1. Larmonie, Nicole S D et al. “Breakpoint sites disclose the role of the V(D)J recombination machinery 
          in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell 
          acute lymphoblastic leukemia.” Haematologica vol. 98,8 (2013): 1173-84
        }
      \end{itemize}
    \end{column}
    \begin{column}{.6\textwidth}
      \begin{figure}
        \centering
        \includegraphics[width=.8\textwidth]{Images/transloc_oncogenes.png}
      \end{figure}
    \end{column}
  \end{columns}
\end{frame}

\begin{frame}{\emoji{dna} Background --- T-cell receptor excision circles (TRECs) }
  \begin{columns}
    \begin{column}{.5\textwidth}
      \begin{figure}
        \includegraphics[width=\textwidth]{Images/trec.png}
      \end{figure}
    \end{column}
    \begin{column}{.5\textwidth}
      \begin{itemize}
        \item During recombination deleted parts of the loci are circulized into TRECs.
        \item Like tansposons the reintegration of TRECs as been suspect to cause 
        \alert{deregulation of targeted genes}.
      \end{itemize}
    \end{column}
  \end{columns}

  \footnotetext{
    \tiny
    Curry, John D et al. “Chromosomal reinsertion of broken RSS ends during T cell development.” The Journal of 
    experimental medicine vol. 204,10 (2007): 2293-303. doi:10.1084/jem.20070583
  }
\end{frame}

{\setbeamercolor{background canvas}{bg=bgturq}
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  \begin{alertblock}{{\centering \large Hypothesis} }
    \begin{itemize}
      \item In T-ALL, we could find with molecular biolgy tools insertions of those TRECs.
      \item With the same tools we also could also find all the translocations which involves the TCR.
    \end{itemize}
  \end{alertblock}
\end{frame}
}

\begin{frame}{\emoji{up-arrow} Material \& Method}
  \begin{itemize}
    \item<1-> We used our extensed collection of \alert{T-ALL samples at diagnostic n = 1533}.
    \item<2-> We designed a NGS capture assay with \alert{capture probes} mapped at multiple parts of de TCR \delta { } locus.
    \item<3-> We developed a specific software to analysed aligned reads and call SV \url{https://github.com/Dr-TSteimle/sv-finder}.
  \end{itemize}
  \begin{figure}
    \centering
    \includegraphics<2>[width=.8\textwidth]{Images/Probes_TRD.png}
    \includegraphics<3>[width=.8\textwidth]{Images/assemblage.png}
  \end{figure}
\end{frame}

\begin{frame}{\emoji{up-arrow} Results --- \textit{TRD} translocations --- Validation cohort}
  \begin{itemize}
    \item To validate our method, we used a previously published cohort of 264 cases analysed with \alert{\textit{TRD} 
    dual-color FISH probe}$^1$.
    \item \alert{Se = 98.1\%} [95\% CI 96-99] and \alert{Sp = 97.7\%}
    \item The 4 FN cases are in fact TRECs insertions inside \textit{ZFP36L2} 
    that couldn't have been seen with FISH !
  \end{itemize}
  \begin{center}
    \includegraphics[width=.3\textwidth]{Images/confusion.png}
  \end{center}
  \vspace{1cm}
  \footnotetext[1]{
    \tiny
    Le Noir, Sandrine et al. “Extensive molecular mapping of TCRα/δ- and TCRβ-involved 
    chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL.” 
    Blood vol. 120,16 (2012): 3298-309. doi:10.1182/blood-2012-04-425488
  }
\end{frame}

\begin{frame}{\emoji{up-arrow} Results --- \textit{TRD} translocations --- Discovery cohort}
  \begin{figure}
    \includegraphics[height=.8\textheight]{Images/distribution.png}
  \end{figure}
\end{frame}

\begin{frame}{\emoji{dart} Results --- \textit{TRD} translocations --- Discovery cohort}
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\end{frame}

\begin{frame}{\emoji{dart} Results --- \textit{TRD} translocations --- Discovery cohort}
  We confirmed all TRECs insertions with sanger sequencing and OGM.
  \begin{figure}
    \includegraphics[width=\textwidth]{Images/ZFP36L2_lolli.pdf}
    \includegraphics[width=\textwidth]{Images/sanger.png}
    \includegraphics[width=.7\textwidth]{Images/bionano_trec.png}
  \end{figure}
\end{frame}

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  \vspace{.5cm}
  \begin{alertblock}{{\centering \large Conclusions} }
    \begin{itemize}
      \item We developed a \alert{highly accurate and sensitive method} that enables precise characterization 
      of \textit{TRD} structural variations. This method can be applied at diagnosis without incurring 
      any additional costs.
      \item Our findings provide confirmation that \alert{recurrent TRECs insertions} are present in cases of 
      T-ALL.
      \item Using our method, we have observed that these recurrent TRECs insertions predominantly 
      disrupt the \textit{ZFP36L2} genes.
      \item The tumor suppressor \textit{ZFP36L2} is well-established to be involved in V(D)J recombination, 
      but further clarifications are needed regarding its specific role in oncogenesis. Our findings will 
      help in the characterization of this tumor suppressor.
    \end{itemize}
  \end{alertblock}
\end{frame}
}

\begin{frame}{\emoji{dart} My PhD --- Rationnal}
  \begin{itemize}
    \item The aforementioned results contribute to the understanding of the dysregulation of proto-oncogenes 
    such as \textit{TAL1}, \textit{TLX1} or \textit{TLX3}.
    \item Despite extensive investigation, the molecular mechanisms underlying the dysregulation of these oncogenes, 
    remain elusive in many cases. 
    \item 
  \end{itemize}
\end{frame}

\begin{frame}{\emoji{dart} Troisième année de thèse -- Hypothèses E et F}
  \begin{itemize}
   \item Selon les oncogènes identifiés lors des étapes précédentes nous explorerons les possibles interventions thérapeutiques
   \item Possibilité de test phramacologiques \textit{ex vivo} et \textit{in vivo}. 
  \end{itemize}
\end{frame}

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  \alert{\textbf{Questions ?}}\\
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%   \frametitle{\emoji{floppy-disk} Méthodes > Calling > Lancet}
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