H3K9 methylation are needed for viral gene transcription in a host cell [42]. To
increase methylation, the virus recruits host cell factor-1 (HCF-1) and an HKMT
complex. Kristie and co-workers showed that LSD1 interacts with the HCF-1
component of the HKMT complex and demethylates H3K9 [41]. They also showed
that blocking LSD1 activity leads to the inhibition of viral gene transcription,
suggesting that LSD1 inhibitors could work as anti-HSV and anti-VZV agents. In
addition to HSV and VZV, LSD1 has also been reported to be involved in latent HIV
infection [43] and hepatitis B virus-induced liver carcinogenesis [44].
4.3 Link of LSD1 to Globin Disorders
The human β-globin locus consists of embryonic, fetal, and adult globin genes that
are expressed during development. Mutations in the globin locus result in β-globin
disorders, such as β-globinopathies, β-thalassemia, and sickle cell disease. Although
the fetal globin genes are autonomously silenced in adult-stage erythroid cells,
mutations lying both within and outside the locus lead to natural variations in the
level of fetal globin gene expression, and some of the mutations ameliorate the
clinical symptoms of β-globin disorders. LSD1 is associated with fetal globin gene
repression in adult-stage erythroid cells. LSD1 has been shown to interact with the
transcription factor BCL11A through a complex containing CoREST [45] and to
mediate part of BCL11A’s strong ɣ-globin gene silencing activity. LSD1 also has
been shown to interact with the TR2-TR4-DNMT1-LSD1 complex, along with
several other corepressor complexes [46]. LSD1 inhibition results in increased
ɣ-globin gene expression in β-globin locus-bearing transgenic mice and cultured
primary human erythroid cells [45, 47], suggesting the effectiveness of LSD1
inhibitors as therapeutic agents for β-globin disorders.
4.4 Link of LSD1 to Metabolic Diseases
It has been suggested that LSD1 is involved in metabolic diseases [48]. LSD1
regulates energy-expenditure genes in adipocytes, and the loss of LSD1 function
in adipocytes induces a number of regulators of energy expenditure and mitochondrial metabolism, resulting in the activation of mitochondrial respiration. The
expression of LSD1-target genes is downregulated in the adipose tissues of mice
on a high-fat diet as compared with that in tissues of mice on a normal diet. This
downregulation is reverted by suppressing the function of LSD1, indicating the
involvement of LSD1 in metabolic diseases.
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increase methylation, the virus recruits host cell factor-1 (HCF-1) and an HKMT
complex. Kristie and co-workers showed that LSD1 interacts with the HCF-1
component of the HKMT complex and demethylates H3K9 [41]. They also showed
that blocking LSD1 activity leads to the inhibition of viral gene transcription,
suggesting that LSD1 inhibitors could work as anti-HSV and anti-VZV agents. In
addition to HSV and VZV, LSD1 has also been reported to be involved in latent HIV
infection [43] and hepatitis B virus-induced liver carcinogenesis [44].
4.3 Link of LSD1 to Globin Disorders
The human β-globin locus consists of embryonic, fetal, and adult globin genes that
are expressed during development. Mutations in the globin locus result in β-globin
disorders, such as β-globinopathies, β-thalassemia, and sickle cell disease. Although
the fetal globin genes are autonomously silenced in adult-stage erythroid cells,
mutations lying both within and outside the locus lead to natural variations in the
level of fetal globin gene expression, and some of the mutations ameliorate the
clinical symptoms of β-globin disorders. LSD1 is associated with fetal globin gene
repression in adult-stage erythroid cells. LSD1 has been shown to interact with the
transcription factor BCL11A through a complex containing CoREST [45] and to
mediate part of BCL11A’s strong ɣ-globin gene silencing activity. LSD1 also has
been shown to interact with the TR2-TR4-DNMT1-LSD1 complex, along with
several other corepressor complexes [46]. LSD1 inhibition results in increased
ɣ-globin gene expression in β-globin locus-bearing transgenic mice and cultured
primary human erythroid cells [45, 47], suggesting the effectiveness of LSD1
inhibitors as therapeutic agents for β-globin disorders.
4.4 Link of LSD1 to Metabolic Diseases
It has been suggested that LSD1 is involved in metabolic diseases [48]. LSD1
regulates energy-expenditure genes in adipocytes, and the loss of LSD1 function
in adipocytes induces a number of regulators of energy expenditure and mitochondrial metabolism, resulting in the activation of mitochondrial respiration. The
expression of LSD1-target genes is downregulated in the adipose tissues of mice
on a high-fat diet as compared with that in tissues of mice on a normal diet. This
downregulation is reverted by suppressing the function of LSD1, indicating the
involvement of LSD1 in metabolic diseases.
202
T. Suzuki