# Spatial heterogeneity of lactylation: insights into gene expression, metabolism, and lactate transport in human embryonic stem cells

## TL;DR

This study explores how lactylation, a new protein modification, affects gene expression and cell behavior in human embryonic stem cells.

## Contribution

The study identifies elevated histone lactylation as a novel feature of human pluripotency.

## Key findings

- Histone lactylation levels are significantly higher in human embryonic stem cells compared to differentiated cells.
- Exogenous lactate increases histone lactylation and affects pluripotency gene expression, including KLF4, KLF5, GBX2, and DMNT3L.
- Lactylation levels are spatially distributed in naïve-like hESC colonies, correlating with SOX2 expression patterns.

## Abstract

Low reprogramming efficiency and high phenotypic variability hinder the regenerative medicine applications of human pluripotent stem cells. Understanding the mechanisms that regulate pluripotency is crucial to overcoming these challenges. This study investigated the relationship between lactylation, a newly identified regulator of gene expression, pluripotency, metabolism, and lactate transport in human embryonic stem cells (hESCs). Histone lactylation levels were significantly higher in hESCs than in differentiated cells. Further, exogenous lactate increased histone lactylation and acetylation levels and altered pluripotency gene expression, notably increasing KLF4, KLF5, GBX2, and DMNT3L in hESCs. Finally, naïve-like hESC colonies exhibited higher lactylation levels peripherally, coinciding with elevated peripheral SOX2 levels. Conversely, lactate transport and production protein levels were higher centrally. This study suggests that elevated histone lysine lactylation levels are a newly identified characteristic of human pluripotency. The spatial distribution findings are consistent with a positive relationship between histone lactylation and SOX2 expression in naïve-like hESCs.

Summary: This article examines the levels and spatial distribution of a newly identified protein modifier, lysine lactylation, and its relationship to cell fate in human embryonic stem cells.