Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice

Reviewer #1 (Public Review):

The goal of the manuscript is a joint analysis of genetic variation, open chromatin, and gene expression in a genetically diverse population of mouse embryonic stem cells.

This is an important manuscript that links gene expression to genetic variants and regions of open chromatin. The mechanisms of genetic gene regulation are essential to understanding how standing genetic variation translates to function and phenotype. This data set has the ability to add substantial insight into the field. In particular, the authors show how the relationships between variants, chromatin, and genes are spatially constrained by topologically associated domains.

The description of the results is hard to follow, specific terms are not well-defined, and the methods section lacks detail. Several fundamental approaches cannot be understood easily without going to references (particularly #6, #15, and #33). The manuscript will benefit from efforts to improve readability.

In addition, the CTCF binding data (ChIP-seq) gets too little attention. The fundamental question of whether regulatory domains vary between individuals is not directly addressed.

Reviewer #2 (Public Review):

The experiments described in the manuscript are well designed and executed. Most of the data presented are of high quality, convincing, and in general support the conclusions made in the manuscript. This manuscript should be of great interest to the field of mammalian gene regulation and the approaches used here can have broader applications in studying genetic and epigenetic regulations of gene expression. The key finding reported here, the importance of 3D chromatin structure in controlling gene expression, although not unexpected, offers a better understanding of the physiological roles of TADs.

Given the complexity of the data and analysis, some clarification is needed to guide readers to better understand the results.