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Investigation of the role of YY1 and PAX1 transcription factors in the molecular mechanisms involved in the Brazilian type of hereditary persistence of fetal hemoglobin

Grant number: 12/07869-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2013
Effective date (End): August 23, 2016
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Fernando Ferreira Costa
Grantee:Carolina Ayumi Braghini
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:08/57441-0 - Clinical, cellular and molecular alterations in hemoglobinopathies and other hereditary hemolytic anemias, AP.TEM
Associated scholarship(s):14/17413-9 - Investigation of transcription factors involved in HBG1 gene expression regulation employing transgenic beta-YAC mice and CD34+ human cells models with Brazilian type of non-deletional hereditary persistence of fetal hemoglobin, BE.EP.DR


The human hemoglobin is the main component of red blood cells, performing the function of transporting oxygen and carbon dioxide to tissues and corresponds to approximately 90% by weight of the cell. In humans there are two hemoglobin switching (inactivation of a gene simultaneously with the activation of another). Chief among them occurs after birth, with reduced expression of gamma globin gene and increased expression of beta globin gene, leading to a progressive decrease of HbF production and increased production of HbA. In HPFH a failure occurs in hemoglobin switching during the postnatal period leading to continued expression of gamma globin gene in adult life, with a consequent increase in the synthesis of gamma globin chains and levels of HbF. The ndHPFH is characterized by a point mutation in the promoter region of the G gamma globin gene (HBG2) or A gamma globin gene (HBG1), resulting in increased levels of HbF, ranging between 3% and 20% heterozygous individuals. The Brazilian type of ndHPFH leads to substitution of a cytosine for a guanine at position -195 of the promoter of the gene HBG1. Studies previously conducted in the Laboratory of Genome Hemoglobin and Blood Center of the University of Campinas (UNICAMP) indicated that the presence of the mutation C> G at position -195 of HBG1 gene promoter disrupts the DNA binding site of the transcription factor YY1 decreasing their interaction, and creates a new site, the central domain binding PAX1, allowing its interaction with the HBG1 gene promoter, which possibly reactivates the expression of this gene, increasing HbF production in adulthood. These results provided the first in vitro evidence for the probable molecular mechanism of gene reactivation in HBG1 Brazilian type of ndHPFH. The objective of this project is to study the role of these transcription factors in ndHPFH-B so that you can access more detailed the molecular mechanisms associated with this disorder.

Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)

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