Page 13 - Haematologica March 2020

Editorials
Figure 1. Cis- and trans-regulation of Lxn gene transcription modulates hematopoietic stem cell function. In trans-regulatory mechanisms of hematopoietic stem cell (HSC) function and number, HMGB2 protein binding to the Lxn gene promoter region positively regulates HSC by suppressing Lxn gene transcription and blocks apoptosis. In the cis-regulatory mechanism of HSC, the G allele in the SNP found in Lxn gene promoter region is associated with higher Lxn gene transcription and lower HSC number, whereas the C allele is associated with suppressed Lxn gene transcription and higher HSC number.
gene transcription may be regulated through epigenetic modification. HMGB2 is also known to regulate senes- cence-associated gene expression by orchestrating the chromatin landscape of the gene loci.16 As the authors dis- cussed, it would be interesting to study the role of Lxn gene regulation by HMGB2 in the context of HSC senes- cence and aging. The SNP identified in this study was in the CG-rich region. Although direct evidence was not shown, these data imply a functional role of the genetic variation, such as SNP, in Lxn gene regulation via DNA methylation. Taken together, this report suggests epige- netic regulation of HSC via Lxn gene transcriptional regu- lation. The molecular mechanism of how epigenetic reg- ulation by HMGB2 protein and genetic variation in the Lxn gene promoter region work together needs to be bet- ter understood.
This report is the first demonstration that genetic vari- ation, especially SNP, is a determinant for the variations among different mouse strains in HSC pool size and func- tion. The authors also discussed a similar observation made in humans,11 opening the possibility that the genetic variation in the Lxn gene promoter region may contribute to the pathogenesis of hematopoietic aplasia/neoplasia, such as bone marrow failure or leukemia. If epigenetic regulation of Lxn gene transcription is involved in these hematopoietic diseases, it could be a new therapeutic tar- get for genetic correction/modification such as genome
editing. Since other genes that regulate HSC function, besides the Lxn gene, could undergo genetic variation through cis-regulatory elements, it would be interesting to characterize SNP in the regulatory region of HSC reg- ulatory genes. This would help to develop therapeutic strategies for personalized medicine.
Acknowledgment
This work was supported by KAKENHI from Japan Society for the Promotion of Science (JSPS) to TM (19K17833), and KAKENHI (17H05651, 18H02843), Princess Takamatsu Cancer Research Fund, MIRAI Research program and Center for Metabolic Regulation of Healthy Aging at Kumamoto University to HT.
References
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3. Wittkopp PJ, Kalay G. Cis-regulatory elements: molecular mecha- nisms and evolutionary processes underlying divergence. Nat Rev Genet. 2011;13(1):59-69.
4. Beerman I, Rossi DJ. Epigenetic Control of Stem Cell Potential dur- ing Homeostasis, Aging, and Disease. Cell Stem Cell. 2015;16(6): 613-625.
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