Permissive epigenomes endow reprogramming competence to transcriptional regulators

Area of Science:

• Stem Cell Biology
• Epigenetics
• Molecular Biology

Background:

• Understanding transcription factor reprogramming competence is key to advancing stem cell technologies.
• Epigenetic modifications significantly influence the efficiency and success of cellular reprogramming.

Purpose of the Study:

• To identify molecular and cellular processes regulating transcription factor reprogramming competence.
• To discover novel factors capable of inducing pluripotency by overcoming epigenetic barriers.

Main Methods:

• Chemical screen targeting major epigenetic pathways in human reprogramming.
• Inhibition of DOT1L-mediated methylation, LSD1, DNA methyltransferases, and histone deacetylases.
• Secondary screen of 98 candidate genes in induced permissive epigenetic states.

Main Results:

• Simultaneous inhibition of epigenetic pathways dramatically enhances reprogramming competence of OCT factors.
• Dismantling of species-dependent reprogramming competence for factors like OCT6, NR5A1, NR5A2, TET1, and GATA3.
• Identification of 25 transcriptional regulators that can functionally replace OCT4 in inducing pluripotency.

Conclusions:

• Epigenetic states are crucial determinants of transcription factor reprogramming efficiency.
• Overcoming epigenetic roadblocks provides a versatile strategy for inducing pluripotency across species.
• This work offers a conceptual framework for understanding transcription factor-mediated reprogramming in relation to donor cell epigenomes.