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Fetal Hemoglobin Gene Regulation Study Points to Potential Therapeutic Targets

NEW YORK — Researchers have mapped the regulatory elements controlling expression of fetal hemoglobin at the single-nucleotide level, uncovering complexities in its regulation that may open new avenues for treating conditions like sickle cell disease.

Fetal hemoglobin, which is composed of two ɣ-globin and two α-globin subunits, is typically expressed by fetal red blood cells in the third trimester. Following birth, the ɣ-globin genes are silenced, paving the way for the expression of β-globin genes and adult hemoglobin. Boosting fetal hemoglobin expression after birth could serve as a treatment for conditions like sickle cell disease.

Using an adenine base editor, researchers from St. Jude Children's Research Hospital mapped the regulatory regions of the BCL11A, MYB-HBS1L, KLF1, and β-like globin genes, which have previously been tied to postnatal expression of fetal hemoglobin. As they reported Thursday in Nature Genetics, the researchers confirmed known and identified new regulatory elements of fetal hemoglobin, which could potentially be targeted for therapy.

"Without the high-throughput system, identifying key regulatory elements is often extremely slow," senior author Yong Cheng, a hematologist and computational biologist at St. Jude, said in a statement.

The researchers turned to the ABEmax base editor to induce thousands of point mutations by converting adenines and thymines to guanines and cytosines, respectively, in predicted cis-regulatory elements (CREs) of the BCL11A, MYB-HBS1L, KLF1, and β-like globin genes. In an email, Cheng noted that the precise nature of the alterations ABE induces enabled them to determine the structure of the regulatory elements at high resolution.

In all, they made 10,156 edits to 307 regulatory elements and worked out the effects of those swaps on the expression of fetal hemoglobin in erythroid cells.

Through this, the researchers validated known regulatory elements of fetal hemoglobin but also uncovered novel ones. For instance, they found strong signals near the promoter region and in a super-enhancer-like region of BCL11A, as well as a potential CREs about one megabase downstream of BCL11A. They likewise identified proximal and distal potential CREs of the KLF1 gene and other elements in the MYB-HBS1L and β-like globin genes regions.

They suggested that the network of CREs influencing BCL11A, MYB-HBS1L, KLF1, and β-like globin genes may represent a regulatory archipelago in which there are multiple, overlapping elements that affect expression during development.

The researchers further explored the epigenomic structures of these regulatory regions by comparing wild-type and base-edited cells. Regions with high effects on fetal hemoglobin expression tended to have higher signals of chromatin accessibility, active histone modifications, and occupancy by key transcription factors, as well as more three-dimensional interactions than other regulatory elements.

By sequencing 454 individuals with sickle cell disease, the researchers subsequently found that the CREs they had identified were linked to low-frequency SNVs in individuals with sickle cell disease with higher-than-expected levels of fetal hemoglobin. This finding indicated that base editing could potentially be used to disrupt CREs that prevent fetal hemoglobin expression, as a means of treating sickle cell disease.

According to Cheng, there are several promising candidates for treatment targets that he and his colleagues are further evaluating. In addition, they plan to expand the coverage of their analysis by using larger pooled gRNA libraries, as well as new editors that recognize PAM sequences to uncover additional candidate elements and variants. At the same time, they are applying their approach to examine regulatory elements that affect other health-related traits.