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Review
. 2024 Nov;46 Suppl 5(Suppl 5):S258-S268.
doi: 10.1016/j.htct.2024.06.001. Epub 2024 Aug 17.

Transcriptional regulators of fetal hemoglobin

Gabriela Pereira Dos Santos  1 , Larissa Teodoro Rabi  2 , André Alves Bezerra  3 , Marcelo Rodrigues da Cunha  3 , Amilton Iatecola  3 , Victor Augusto Ramos Fernandes  4
Affiliations
Review

Transcriptional regulators of fetal hemoglobin

Gabriela Pereira Dos Santos et al. Hematol Transfus Cell Ther. 2024 Nov.

Abstract

Sickle cell anemia is a hereditary disease caused by sickle-shaped red blood cells that can lead to vaso-occlusive crises. Treatment options are currently limited, highlighting the need to develop new clinical approaches. Studies demonstrated that elevated levels of fetal hemoglobin (Hb F) are associated with a reduction of mortality and morbidity in sickle cell anemia patients. In light of this, researchers have been trying to elucidate the transcriptional regulation of Hb F to develop new therapeutic interventions. The present study aimed to present the main transcription factors of Hb F and discuss the clinical feasibility of these molecular targets. Two search strategies were used in the PubMed, SciELO, and LILACS databases between July and August 2023 to conduct this review. Manual searches were also conducted by checking references of potentially eligible studies. Eligibility criteria consisted of clinical trials and cohort studies from the last five years that investigated transcription factors associated with Hb F. The transcription factors investigated in at least four eligible studies were included in this review. As a result, 56 eligible studies provided data on the BCL11A, LRF, NF-Y, GATA1, KLF1, HRI, ATF4, and MYB factors. The studies demonstrated that Hb F is cooperatively regulated by transcription factors with the BCL11A factor appearing to be the most specific target gene for γ-globin induction. Although these data are promising, there are still significant gaps and intervention limitations due to the adverse functions of the target genes. New studies that clarify the aspects and functionalities of Hb F regulators may enable new clinical approaches for sickle cell anemia patients.

Keywords: Fetal hemoglobin; Gamma-globin; Gene therapy; Sickle cell anemia; Transcription factors.

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Conflict of interest statement

Conflicts of interest The authors declare no conflicts of interest.

Figures

Fig. 1
Figure 1
Flowchart demonstrating the search processes applied to identify potentially eligible studies.
Fig. 2:
Figure 2
Flowchart demonstrating the identifying, screening, and selecting process of the studies.
Fig. 3:
Figure 3
Transcriptional repression of Hb F: illustration demonstrating locus control region (LCR) inducing fetal-to-adult hemoglobin switching through chromosomal looping.
Fig. 4:
Figure 4
Transcription Activation of Hb F: stress erythropoiesis and a locus control region (LCR) performing chromosomal looping to attract GATA1 and NF-Y activators.
Fig. 5:
Figure 5
Ex vivo and In vivo interventions employed for gene editing Created with Biorender.com.
See this image and copyright information in PMC

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