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A study published in Cell Reports indicates that BET inhibitors can improve the reprogramming of human fibroblasts to create induced pluripotent stem cells (iPSCs).
According to researchers, this improvement in reprogramming can increase the yield of iPSCs from fibroblasts and enhance the quality of the iPSCs by ensuring that more somatic genes are efficiently turned down or turned off during reprogramming.
Study author Kejin Hu, PhD, of the University of Alabama at Birmingham, said the factors that are commonly used to create iPSCs from fibroblasts face a reprogramming barrier.
“If we can lower the barrier, we can enhance the reprogramming efficiency,” he explained. “My strategy is to use chemicals to erase the transcriptional program specific to the starting cells.”
Dr Hu and his colleagues found that BET-specific chemical inhibitors were effective in this regard.
For example, a low concentration of the BET inhibitor JQ1:
- Downregulated 390 fibroblast-specific genes when applied to naïve human fibroblasts
- Downregulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming
- Increased the efficiency of successful reprogramming of human fibroblasts to iPSCs by 20-fold.
The researchers also found that fibroblasts change shape when treated with JQ1.
The cells transform from a long spindle shape to polygonal or rounded cells, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are downregulated by JQ1.
Dr Hu proposed the following model to explain his team’s findings.
During normal cell division, active fibroblast genes are “bookmarked” by the attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin.
At the start of interphase, these bookmarks guide the polymerase back to the genes, and they are transcribed by RNA Polymerase II.
In contrast, when JQ1 is added, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division.
This “erases” the epigenetic memory of fibroblast gene expression, which, in turn, results in loss of fibroblast gene transcription when interphase returns.
This also increases the success of reprogramming into iPSCs. 
Image from Salk Institute
A study published in Cell Reports indicates that BET inhibitors can improve the reprogramming of human fibroblasts to create induced pluripotent stem cells (iPSCs).
According to researchers, this improvement in reprogramming can increase the yield of iPSCs from fibroblasts and enhance the quality of the iPSCs by ensuring that more somatic genes are efficiently turned down or turned off during reprogramming.
Study author Kejin Hu, PhD, of the University of Alabama at Birmingham, said the factors that are commonly used to create iPSCs from fibroblasts face a reprogramming barrier.
“If we can lower the barrier, we can enhance the reprogramming efficiency,” he explained. “My strategy is to use chemicals to erase the transcriptional program specific to the starting cells.”
Dr Hu and his colleagues found that BET-specific chemical inhibitors were effective in this regard.
For example, a low concentration of the BET inhibitor JQ1:
- Downregulated 390 fibroblast-specific genes when applied to naïve human fibroblasts
- Downregulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming
- Increased the efficiency of successful reprogramming of human fibroblasts to iPSCs by 20-fold.
The researchers also found that fibroblasts change shape when treated with JQ1.
The cells transform from a long spindle shape to polygonal or rounded cells, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are downregulated by JQ1.
Dr Hu proposed the following model to explain his team’s findings.
During normal cell division, active fibroblast genes are “bookmarked” by the attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin.
At the start of interphase, these bookmarks guide the polymerase back to the genes, and they are transcribed by RNA Polymerase II.
In contrast, when JQ1 is added, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division.
This “erases” the epigenetic memory of fibroblast gene expression, which, in turn, results in loss of fibroblast gene transcription when interphase returns.
This also increases the success of reprogramming into iPSCs.
Image from Salk Institute
A study published in Cell Reports indicates that BET inhibitors can improve the reprogramming of human fibroblasts to create induced pluripotent stem cells (iPSCs).
According to researchers, this improvement in reprogramming can increase the yield of iPSCs from fibroblasts and enhance the quality of the iPSCs by ensuring that more somatic genes are efficiently turned down or turned off during reprogramming.
Study author Kejin Hu, PhD, of the University of Alabama at Birmingham, said the factors that are commonly used to create iPSCs from fibroblasts face a reprogramming barrier.
“If we can lower the barrier, we can enhance the reprogramming efficiency,” he explained. “My strategy is to use chemicals to erase the transcriptional program specific to the starting cells.”
Dr Hu and his colleagues found that BET-specific chemical inhibitors were effective in this regard.
For example, a low concentration of the BET inhibitor JQ1:
- Downregulated 390 fibroblast-specific genes when applied to naïve human fibroblasts
- Downregulated 651 fibroblast-specific genes when applied to human fibroblasts during reprogramming
- Increased the efficiency of successful reprogramming of human fibroblasts to iPSCs by 20-fold.
The researchers also found that fibroblasts change shape when treated with JQ1.
The cells transform from a long spindle shape to polygonal or rounded cells, which shows loss of fibroblast identity and transition to pluripotent stem cells. Presumably, genes that are needed to maintain the spindle shape are downregulated by JQ1.
Dr Hu proposed the following model to explain his team’s findings.
During normal cell division, active fibroblast genes are “bookmarked” by the attachment of BET proteins to acetylated chromatin during the mitotic phases, while RNA Polymerase II drops off of the chromatin.
At the start of interphase, these bookmarks guide the polymerase back to the genes, and they are transcribed by RNA Polymerase II.
In contrast, when JQ1 is added, the active fibroblast genes are de-bookmarked by the interaction of JQ1 with the BET proteins during the mitotic phases of cell division.
This “erases” the epigenetic memory of fibroblast gene expression, which, in turn, results in loss of fibroblast gene transcription when interphase returns.
This also increases the success of reprogramming into iPSCs.