The study of genetic factors influencing blood diseases has taken significant strides following the advent of genome-wide association studies (GWAS), which have identified numerous genetic variants associated with conditions such as sickle cell anemia and beta-thalassemia. One such area of interest is the HBS1L-MYB intergenic region, which houses several single nucleotide polymorphisms (SNPs) impacting fetal hemoglobin levels—an important trait relating to the severity of these hemoglobinopathies.
Research looks closely at the MYB − 84kb enhancer, analogous to the mouse MYB − 81kb enhancer, amid claims it plays a key role in the regulation of MYB and, by extension, influences levels of fetal hemoglobin. Though the MYB enhancer is highly conserved across species, the functional mechanisms behind how genetic variants therein affect disease susceptibility have remained largely unexplored.
To fill this gap, researchers have generated Myb − 81kb enhancer knock-out mice. The goal has been to elucidate the functional consequences of deleting this enhancer on erythroid development and disease severity, which reflects broader efforts within genetic research to delineate the impact of these non-coding regions.
This animal model revealed initially surprising findings. Contrary to expectations, the deletion of the MYB − 81kb enhancer did not significantly impair overall hematopoiesis, meaning the body’s blood cell production mechanism remained largely intact. Instead, researchers observed specific changes: the percentage of megakaryocyte-erythroid bipotent progenitors decreased alongside changes to the profile of differentiative erythroid cells. Surprisingly, the number of differentiative populations of red blood cells did not alter much, indicating the systemic adaptability of these cellular systems under altered genetic conditions.
Notably, the study also pointed to increased mean corpuscular volume (MCV) values among the knock-out mice, identified through comprehensive blood parameters analysis. The researchers speculated this could be linked to reduced MYB levels affecting progenitor capacity during acute conditions, which may be critically relevant for patients suffering from beta-thalassemia.
Further investigations revealed knock-out animals experienced delayed recovery following induced hemolytic stress but nonetheless managed to eventually restore normal levels of red blood cells. Mice lacking the − 81kb enhancer took longer to overcome anemia than their control counterparts, but after about two weeks, their recovery began to mirror expected patterns of blood regeneration.
Elucidation of the molecular mechanisms underlying the observed variations revealed decreased levels of MYB expression among immature progenitors. Both embryonic globin genes like Hbb-bh1 and adult β-globin genes exhibited significant decreased expression, indicating the Myb − 81kb enhancer plays a nuanced regulatory role over time as hemoglobin types switch from fetal to adult forms.
Interestingly, crossbreeding these knock-out mice with β-thalassemia models exposed potential therapeutic benefits. Mice exhibiting the enhanced model demonstrated observable reductions in splenomegaly and improvements across several erythroid parameters, albeit not entirely alleviating the disease phenotype, as seen with typical control animals. This finding suggests the knockout of the − 81kb enhancer could beneficially modulate disease symptoms for some patients.
The study concludes with optimism surrounding the potential for these insights to inform future therapeutics targeting the MYB manipulation, particularly due to the promise showcased through the Myb − 81kb enhancer model as it consistently shed light on the complex regulatory network involved in erythropoiesis.
This work marks substantial progress toward unraveling the pathways shaped by GWAS findings, illuminating how non-coding regions of the genome might be strategically targeted to ameliorate conditions linked to the persistence of fetal hemoglobin and combat hemoglobin disorders.