Imagine the genome as a city with different neighborhoods, each having its function. Topologically associating domain (TAD) boundaries are like the fences that separate these neighborhoods, maintaining distinct regulatory territories. Disruption of these boundaries may interfere with regular gene expression and cause diseases, but the full impact remains unclear.

Researchers utilized CRISPR genome editing in mice to investigate the consequences of deleting eight TAD boundaries. All deletions led to noticeable molecular or organismal phenotypes, including chromatin interaction or gene expression changes, reduced viability, and anatomical abnormalities.

In 88% of cases, local 3D chromatin architecture was altered. This included merging TADs and changed contact frequencies within adjacent TADs. Additionally, 63% of the examined loci exhibited increased embryonic lethality or developmental issues. For instance, a TAD boundary deletion near Smad3/Smad6 led to complete embryonic lethality, while another near Tbx5/Lhx5 caused severe lung malformation.

This study highlights the importance of TAD boundary sequences for proper genome function and organism development. It also emphasizes the need to consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening. By understanding the impact of TAD boundary disruptions, we can better diagnose and potentially treat genetic disorders.

Source: https://www.nature.com/articles/s42003-023-04819-w#Sec8