# Basis for lineage-determining pioneer factors targeting distinct repressed chromatin states

## TL;DR

The paper explores how pioneer transcription factors access and modify different types of silent chromatin to influence cell fate and development.

## Contribution

The study reveals how DNA binding domains and non-DBD domains determine targeting of distinct repressed chromatin states by pioneer factors.

## Key findings

- The DNA binding domain type determines whether pioneer factors target compact chromatin or accessible chromatin.
- Non-DBD domains enable targeting of chromatin marked by H3K9me3 or H3K27me3.
- Fusing non-DBD segments to SOX2 improves its binding and reprogramming efficiency in heterochromatin.

## Abstract

Pioneer transcription factors target transcriptionally silent chromatin, thereby enabling gene activation in development, regeneration, and cell reprogramming. However, silent chromatin is heterogeneous, varying in nucleosome stability, nucleosome compaction, and repressive histone modifications, and how pioneer factors may differentially overcome these different chromatin barriers is unknown. We systematically compared the chromatin targeting of 13 embryonic transcription factors and found that the DNA binding domain (DBD) type predicts whether a pioneer factor targets low-turnover nucleosomes in compact chromatin, dynamic nucleosomes in compact chromatin or functions as a nonpioneer factor targeting accessible chromatin. By contrast, non-DBD domains enable targeting of repressed chromatin marked by H3K9me3 or H3K27me3. Fusions of different non-DBD segments of heterochromatin-targeting pioneer factors to the transcription factor SOX2 can expand binding of SOX2 target motifs within heterochromatin and improve cellular reprogramming. Our study unveils how different forms of silent chromatin are coordinately targeted by lineage-specifying factors.

Developmental transcription factors display a range of targeting H3K9me3 heterochromatin to open chromatin, for cell fate changes.