Epigenetic inheritance is gated by naïve pluripotency and Dppa2

Area of Science:

• Epigenetics and Developmental Biology
• Chromatin Biology
• Mammalian Genetics

Background:

• Environmental factors can induce epigenetic changes, but their heritability across generations in mammals remains poorly understood.
• The epigenome's role in transmitting acquired traits and the mechanisms constraining this in mammals require elucidation.

Purpose of the Study:

• To investigate the inheritance dynamics of engineered heterochromatin (epialleles) during mammalian development.
• To identify factors and contexts that permit or restrict epigenetic inheritance.
• To understand the safeguards against transgenerational epigenetic memory in mammals.

Main Methods:

• Utilized precision epigenetic editing and forced Xist activity to create de novo heterochromatin domains.
• Tracked inheritance of these epialleles in a developmental model.
• Employed genome-wide CRISPR screening to identify restricting factors.
• Studied inheritance patterns during lineage specification and in vivo development.

Main Results:

• Naïve pluripotent cells actively erase ectopic heterochromatin, acting as an intergenerational safeguard.
• Acquired chromatin states can be probabilistically inherited upon lineage specification, especially under selective pressure (e.g., p53 silencing).
• Identified molecular factors, including Dppa2, that restrict heritable epigenetic memory in pluripotent cells.
• Demonstrated that removing Dppa2 enables epigenetic inheritance independent of DNA sequence.

Conclusions:

• Epigenetic inheritance in mammals is mechanistically constrained, with active erasure in early development.
• Specific developmental contexts and the removal of key chromatin factors can enable epigenetic inheritance.
• This study provides insights into the regulation of transgenerational epigenetic memory and its potential.