MSGID: 1:317/3 646ee498   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Epigenetic landscape modulates pioneer transcription factor binding   
      
      
     Date:   
         May 24, 2023   
     Source:   
         St. Jude Children's Research Hospital   
     Summary:   
         Scientists studied how the epigenetic landscape influences the   
         binding of pioneer transcription factors, affecting access to DNA.   
      
      
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   FULL STORY   
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   Like thread tightly wrapped around a spool, DNA is wrapped around histones   
   and packaged into structures called nucleosomes. Scientists at St. Jude   
   Children's Research Hospital are exploring how a type of transcription   
   factor called a pioneer transcription factor accesses DNA even when   
   it is tightly wound. Their work revealed how the epigenetic landscape   
   influences transcription factor binding. Problems with transcription have   
   been implicated in numerous cancers, so this more detailed understanding   
   of the process may aid in developing future therapeutics. The study was   
   published today in Nature.   
      
   The nucleosome packaging of DNA can physically block transcription   
   factors that regulate gene expression from accessing their binding   
   sites. Restricting access to DNA is an integral part of how transcription   
   is regulated. However, pioneer transcription factors can bind to their   
   target piece of DNA even within compacted chromatin and are also known   
   to promote the binding of other transcription factors.   
      
   Among pioneer transcription factors are the so-called Yamanaka factors   
   which include Oct4 and are used to induce pluripotency (the ability to   
   give rise to different cell types). How pioneer transcription factors   
   access tightly wound DNA was unclear. To better understand the process,   
   scientists at St. Jude used cryo-electron microscopy (cryo-EM) and   
   biochemistry to investigate how Oct4 interacts with nucleosomes.   
      
   "Building on prior work to understand the dynamic behavior of nucleosomes,   
   we wanted to understand how other factors might utilize those dynamic   
   changes to access chromatin," said corresponding author Mario Halic,   
   Ph.D., St.   
      
   Jude?Department of Structural Biology. "Oct4 did not bind where we   
   anticipated it might -- rather than binding inside the nucleosome, we   
   found that it bound a little bit outside."  "One of the main findings is   
   that epigenetic modifications can affect transcription factor binding   
   and cooperativity," Halic added. "The existing epigenetic state of   
   chromatin can determine how transcription factors will cooperatively bind   
   to chromatin."  The epigenetic impact Results show that the first Oct4   
   molecule binding "fixes" the nucleosome in a position that increases   
   the exposure of other binding sites, thus promoting the binding of   
   additional transcription factors and explaining transcription factor   
   cooperativity.?They also found that Oct4 contacts histones, and these   
   interactions promote chromatin opening and influence cooperativity. Their   
   work also showed that modifications at histone H3K27 affect the   
   positioning of DNA by Oct4. These findings explain how the epigenetic   
   landscape can regulate Oct4 activity to ensure proper cell programming.   
      
   Notably, the researchers used endogenous human DNA sequences instead of   
   artificial sequences to assemble their nucleosomes. This allowed them   
   to study the dynamic nature of the nucleosome, despite it being more   
   challenging to work with.   
      
   "In this work, we used real genomic DNA sequences to study transcription   
   factors in the context of where they function," said first author Kalyan   
   Sinha, Ph.D., St. Jude Department of Structural Biology. "This strategy   
   allowed us to discover that the first binding event of Oct4 positions   
   the nucleosomal DNA in a manner that allows cooperative binding of   
   additional Oct4 molecules to internal sites. In addition, we observed   
   exciting interactions with histone tails and have seen that histone   
   modifications can alter those interactions.   
      
   Together, these findings provide new insights into the pioneering   
   activity of Oct4."  "Histone modifications affect how DNA is positioned   
   and how transcription factors can bind cooperatively," Sinha added,   
   "which means in cells, if you have the same DNA sequence, different   
   epigenetic modifications can result in different, combinatorial effects   
   on transcription factor binding."   
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Epigenetics # Human_Biology # Genes # Workplace_Health   
                   # Amyotrophic_Lateral_Sclerosis # Nervous_System #   
                   Multiple_Sclerosis_Research # Forensics   
       * RELATED_TERMS   
             o DNA_microarray o Fetus o DNA_repair o Epidemiology o   
             Introduction_to_genetics o DNA o Genetically_modified_organism   
             o Trait_(biology)   
      
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   Story Source: Materials provided by   
   St._Jude_Children's_Research_Hospital. Note: Content may be edited for   
   style and length.   
      
      
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   Journal Reference:   
      1. Kalyan K. Sinha, Silvija Bilokapic, Yongming Du, Deepshikha Malik,   
      Mario   
         Halic. Histone modifications regulate pioneer transcription factor   
         cooperativity. Nature, 2023; DOI: 10.1038/s41586-023-06112-6   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230524182037.htm   
      
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