Modeling uniquely human gene regulatory function via targeted humanization of the mouse genome

Emily V. Dutrow, Deena Emera, Kristina Yim, Severin Uebbing, Acadia A. Kocher, Martina Krenzer, Timothy Nottoli, Daniel B. Burkhardt, Smita Krishnaswamy, Angeliki Louvi and James P. Noonan ()
Additional contact information
Emily V. Dutrow: Yale School of Medicine
Deena Emera: Yale School of Medicine
Kristina Yim: Yale School of Medicine
Severin Uebbing: Yale School of Medicine
Acadia A. Kocher: Yale School of Medicine
Martina Krenzer: Yale School of Medicine
Timothy Nottoli: Yale School of Medicine
Daniel B. Burkhardt: Yale School of Medicine
Smita Krishnaswamy: Yale School of Medicine
Angeliki Louvi: Yale School of Medicine
James P. Noonan: Yale School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The evolution of uniquely human traits likely entailed changes in developmental gene regulation. Human Accelerated Regions (HARs), which include transcriptional enhancers harboring a significant excess of human-specific sequence changes, are leading candidates for driving gene regulatory modifications in human development. However, insight into whether HARs alter the level, distribution, and timing of endogenous gene expression remains limited. We examined the role of the HAR HACNS1 (HAR2) in human evolution by interrogating its molecular functions in a genetically humanized mouse model. We find that HACNS1 maintains its human-specific enhancer activity in the mouse embryo and modifies expression of Gbx2, which encodes a transcription factor, during limb development. Using single-cell RNA-sequencing, we demonstrate that Gbx2 is upregulated in the limb chondrogenic mesenchyme of HACNS1 homozygous embryos, supporting that HACNS1 alters gene expression in cell types involved in skeletal patterning. Our findings illustrate that humanized mouse models provide mechanistic insight into how HARs modified gene expression in human evolution.

Date: 2022
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27899-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27899-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27899-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().