Review Article
Role of Sirtuin6 in Reproduction
Maira Hassan
Department of biological sciences, superior university lahore, bschm-f20-022@superior.edu.pk
Abstract
Sirtuin6 is a protein group of Nicotinamide adenine dinucleotide (NADs)
dependent histone deacetylases which prevent from age associated diseases. In female
reproductive system, sirtuin6 play an important role in oogenesis and prevent from ovarian
cancer. It prevents from the preterm labors in females and promote the normal vaginal birth
and protect against age related-associated diseases and sirtuin6 promotes the terminal events of
the cervical ripening and contractions of uterus. Activation of sirtuin6 is beneficial in the
management and cure the miscarriage. Bacterial infection low the declaration in sirtuin6 and
in the consequences, not normal delivery occurs. In vitro fertilization the female which has no
fertility do fertilization in the outside. Sirtuin6 have the association in vitro fertilization.
Sirtuin6 reduces the cancer in the endometrium to kill the muted cells which cause the cancer
in the endometrium. In male reproductive system, it promotes the spermatogenesis. Functional
and morphological changes in testis may decrease the production of male reproductive
hormones which play an important role in the spermatogenesis in males and testosterone which
control the secondary sex characteristics in males. Those mice which have the positive level of
sirtuin6 have the normal spermatogenesis (production of round and elongated sperms) while
those mice which have the negative or low level of sirtuin6 causes morphological abnormalities
in acrosomal head, flagella etc. and these mice die in 4 weeks and sometimes after 8 weeks.
So, sirtuin6 have the vital role in both male and female reproductive systems.
Key words
Sirtuin6, ovarian cancer, oogenesis, spermatogenesis, reproduction, cell division,
fertility.
Introduction
The Nicotinamide adenine dinucleotide (NAD) dependent histone deacetylase protein family
known as sirtuins (SIRTs) prevents from age associated illness. Seven distinct members of the
SIRT group have been clarified in mammals each with unique subcellular locations, tissue
selectivity, activities, as well as roles (Kawahara, Michishita et al. 2009). SIRT2 is in the
cytoplasm, SIRT1 is in the nucleus, SIRT6 is found in the mitochondria of the cell, SIRT7 is
found in the cytoplasm. The cell cycle, stress signaling, cell survival and genomic strength are
all under the general control of the SIRT. The function of the female reproduction is regulated
by these SIRT. Aging females see a drop level in ovarian follicle pool size i.e., the structure in
which the female germ cells development occur, oocytes quality which means the normal
development of oocytes and oocyte has the normal fertilization and ultimately normal
pregnancy occur and the production of oocytes (Lappas 2012). Ovarian aging in which with
the increasing age the female ovary has not proper functioning as a result the production of
female hormone like follicle stimulating hormone (which stimulate the development of oocyte)
estrogen and progesterone which play an important role in the thickening of the walls of the
uterus called endometrium are decreased in its concentration is the name for this process. A
SIRT6 Gene produces the stress- responsive protein known as sirtuin 6. SIRT6 is found in the
nucleus of the cell, where this participates in the genetic material either DNA or RNA repair as
well as the production of metabolic genes the genes which control the metabolism. It can be
found in the wreckage areas (the area which is injured in any reason and in this area the sirtuin
6 is present to cure the area). Sirtuin6 (SIRT6) is the histone deacetylase that is essential for
the pathways that control cellular homeostasis ( the process in which maintain the concentration
of solutes inside the cell). It is involved in the disorders that are associated with aging(the
diseases which is occur with the progression of age). The deacetylase activity of SIRT6
promotes telomeres integrity by the exerting high substrate selectivity, preserving the
chromatin functions(Mishra, Retherford et al. 1999). As a result, the SIRT6 relays the cell
senescence by promoting oxidative stress resistance, reducing the DNA damage, and
maintaining the telomeres length( the protective caps which is present on the end of the DNA
strand which is important for life).
Sirtuin6 in Female Reproduction
Role of Sirtuin6 in ovarian cancer
Mutation or cancer in the ovary is the eighth progressive reason in the mutation which is
leading fatal or death in the females and has the fatality rate (the rate in which the person
infected by those diseases which is end up by death) that is comparatively greater than that of
the other cancers of the female reproductive organ such as ovaries(Wild 2014). The existence
of an individual with the increasing the cancer of the ovary is the restricted, in addition to
ongoing improvements in survival for those with ovarian cancer in the conjunction with the
recent developments in the targeted therapy (Parvinen 1982). SIRT6 deficiency in the mice are
associated to the symptoms of the Early ageing and the mice will infected by many diseases
and ultimately deaths occur. The ovary is the organ in the women that ages the fastest since
ovarian functions end with the menopause(about at the age of 50). During at every stage of
development, SIRT6 is associated to the chromatin. A newly discovered regulator of female
reproductive health is SIRT6 (Han et Al., 2015). SIRT6 siRNA- mediated depletion is the
correlated with the decreased meiosis development and the leading generation of the aneuploid
MII egg during in the outside development of the mice eggs or oocytes. SIRT6 knockout
oocytes exhibit abnormal K- MT attachments, larger spindles, and chromosomal misalignment
at metaphase l . Moreover, IVF- derived embryos from the meiosis II in the oocytes are the low
successful in the reaching the developing stage of the blastocyst (Ge et al., 2019). This is
shown that the role of it is in the cells of somatic chromatin (Tasselli et Al., 2017), every stage
of the oocytes maturation that has been measured features SIRT6 as a chromatin- bound
protein. SIRT6 controls the epigenetic markers proteins H3K56ac, H3k9ac, as well as
H3k18ac, in somatic cells. H3k9ac as well as H3K56ac, however are the unaltered in the SIRT6
depleted oocytes, on the other hand H4k16ac is markedly elevated (Han et Al., 2015). It is
possibility that the H3k9ac expression by the SIRT6 Gene happens selectively at particular
genomic locations or may the other members of the sirtuin could make up for the absence of
activity of the sirt6 gene. This finding may be also the point to the possibility that SIRT6
epigenetic target vary according to the cell type. Although it is epigenetic prior regulation of
the H3k18ac at the chromatin in the pericentromeric region, SIRT6 is a crucial mitotic regulator
(Tasselli et Al., 2016). In order to understand either SIRT6 recessive H3K18ac in order to plays
a same role in the cells which do meiosis, it will be a vital to understand how epigenetic
alternations at the chromatin which is located in the centromere which is assumed to a crucial
to the development of the amphitelic K-MT connection. Telomeres are defective in mouse
oocytes have lower level of the SIRT6 protein, and SIRT6 reintroduction combined with IVFproduces the embryos with the longer telomeres, less DNA damage at telomeric locations, and
improved the overall survival. After the ovarian hyperstimulation, SIRT6 levels were
unchanged, but considerably lower in the expected females than in the
non-expected
females(Burke, Orr et al. 2014).
Summary of Sirtuin6's Involvement in Reproductive Process
Table 1:
Oocyte maturation
Sirtuin6 plays a crucial role in regulating the
maturation process of oocytes. It helps in
maintaining the proper balance of proteins
and enzymes involved in the oocyte
development. This ensures that the oocytes
are fully mature and capable of successful
fertilization.
Embryo development
Sirtuin6 is involved in the development of
embryos. It helps in regulating various
cellular processes during embryogenesis,
such as cell division, differentiation, and
growth. Sirtuin6's activity is important for
the proper development and viability of
embryos.
Fertility
Sirtuin6 has been linked to fertility and
reproductive health. It is involved in
maintaining the overall health and function
of reproductive cells, including sperm and
eggs. Sirtuin6 activity is crucial for optimal
fertility and successful reproduction
Role of Sirtuin6 in Oocytes
It is common to know that the aging mammals have lower-quality oocytes(the oocyte do not
function normally or they may have the abnormalities as a result no normal fertilization and
pregnancy). The fundamental mechanism has not yet been investigated, though. It is reported
that the declaration of the protein of sirt6 is reduced in eggs and in the developing fetus from
aged mice (which are 42–45 weeks old), added to the abridge in the telomere and the genetic
material trauma( in which the trauma is transferred to the next generation from the previous
generation). In addition to, it was shown that the targeted oocyte reduction of SIRT6 causes the
dysfunctional telomeres and early embryonic apoptosis (the death of the cell occurs in
controlled way or with the program), which results in the developmental lag and cytoplasmic
fragmentation. Interestingly, it is to know that the upregulation of SIRT6 gene in old egg cells
or oocytes encourages the telomere lengthening in the 2-cell developing embryos as well as
reduces the frequency of the blastomere apoptosis(Han, Ge et al. 2015).Additionally, it has
been found that the SIRT6 reduction is a key link between maternal ageing and the control of
oocyte or embryo quality. This indicates that SIRT6 regulates telomere function during oocyte
maturation and embryonic development (Eppig 1996).SIRT6 play an important role in the
reproduction of humans as well as it may be involved in the development of oocytes as well as
in vitro clinical fertilization for pregnancy (IVF)(Yamada-Fukunaga, Yamada et al. 2013).
Role of Sirt6 in Endometrial Cancer
The most prevalent gynecologic disease, endometrial cancer, is on the rise in every country
(Burke, Orr et al. 2014). There is a close connection between uterine cancer ( abnormal division
of the cells) and metabolism. Obesity and diabetes mellitus (DM) have proportional risks for
endometrial cancer that are, respectively, 1.8 and 1.5 times higher (Liao, Zhang et al. 2014),
07:43 PM. Endometrial cancer is brought on by these variables, which also cause insulin
resistance (Mu, Zhu et al. 2012).SIRT6 protected against heart failure by blocking the
IGF1RAKT-mTOR pathway, according to research (Sundaresan, Vasudevan et al. 2012).Due
to the frequent activation of the PI3K-mTOR pathway in uterine cancer, SIRT6 may stop the
disease's progression.Sirt6 inhibition in the cell may cause the cell death. Sirt6 reduces the
development the cancer of the lining of uterus called endometrium by the process of the death
of the muted cells.
Role of Sirtuin6 in Placenta or Preterm labor
Preterm delivery is a significant global health issue. Both mothers and the newborns are
affected by the preterm delivery. Anti-inflammatory characteristics are possessed by the
SIRT6.The deficiencies in the mice exhibit a degenerative phenotype and as a result the
structural abnormalities occurs in an individual with the signs of the early senescence and these
person's do not alive more and ultimately death occurs at the 4 to 5 weeks old (Lappas, Mitton
et al. 2011).In several tissues, these animals also exhibit the increased expression of the NFKB
dependent genes. Due to the signs of an inflammatory response present in the human labor, the
SIRT6 may be implicated in this process (Lappas and Rice 2007). In this study, SIRT6
expression in foetal membranes will be examined for its effect on the spontaneous preterm
labour.SIRT6 mRNA and protein levels will be evaluated by quantitative real-time PCR
(qRTPCR) and Western blot analysis, respectively. Immunohistochemistry will be used to
identify SIRT6's cellular distribution in the membranes of human foetal tissue. In the
embryonic membranes, SIRT6 controls prolabor mediators. He documented a reduction in the
SIRT6 expression in the fetal membranes from the premature pregnant mothers. The SIRT6
controls the premature labor ( the labor which occurs before the time of normal delivery) by
causing the membranes to rupture. He proposed that SIRT6 expression is down regulated
during preterm labor (caused by infection), which increases NFKB activity and the production
of proinflammatory cytokines, prostaglandins, and MMP9. The foetal membrane rupture
caused by the up regulation of these prolabor mediators ultimately results in labor and delivery.
Further investigation is required to establish whether SIRT6 controls the cervical ripening as
well as uterine contractions, which are two other terminal processes of labor. It must be
hypothesized, that SIRT6 expression is flat-regulated during miscarriage or labor in early
stage(which is caused by the infection), which increases the activity of NFKB and its target
products, namely the proinflammatory cytokines, prostaglandins are the hormone which is
present at the sites of injury and play an important role in the blood clotting at the site of injury,
and the production of MMP9. Excitingly, the SIRT6 activation may be helpful in the prevention
and the treatment of the preterm labor, according to the impacts of SIRT6 overexpression in
the function of the SIRT6 plays in the embryonic membrane (amnion) which surrounded the
embryo and contain fluid which prevent from shock chorion which is involved in gaseous
exchange and allantois which is involved in the storage of waste material are rupturing.
It is also suggested that the premature labor mediators, such as bacterial infections, reduce the
expression of the SIRT6 gene in the extra embryonic membranes in the human. As NFKB and
its target products—proinflammatory cytokines, prostaglandins, and proteases—activate more
frequently, the result is before the time premature burst of the extra embryonic membranes
(pPROM) and ultimately birth before the nine months. Any bacterial infection is the mediators
of the premature labor or delivery. If the level of sirtuin6 is decreased then the pro inflammatory
in the division of cytoplasm and other factors and as result the extra embryonic membranes like
chorion which is involved in the gaseous exchange, amnion which surround the fetus and
provide amniotic fluid and allantois which is involved in the storage of waste materials are
ruptured and as a result the delivery of the fetus occurs before the 9 months or miscarriage.
Role of Sirtuin6 in Vitro Fertilization
In outside fertilization (IVF) the fertilization in which are unable to attain the normal delivery
due to any reason and in this way the fertilization of egg and sperm occurs outside the female
body and after sometime is implanted to the other female for the further development and it is
a common and effective method for treating infertility. During vitro fertilization, sperm from
outside the uterus fertilize an embryo (Bódis, Sulyok et al. 2019).The concept entails examine
as well as promoting ovulation in a female, removing an egg or eggs from a woman's ovaries
and enabling sperm to fertilize them in a liquid inside a lab. In order to create a successful
pregnancy, the egg which is fertilized(zygote) is placed in the culture media for 2 to 6 days in
the media of growing before being introduced in the uterus of the similar or different females
(Women's and Health 2004). It is investigated that the relationship between SIRT6 and the
hormonal state of women undergoing in vitro fertilization. The nicotinamide adenine
dinucleotide (NAD+)-recessive deacetylase family includes the SIRT6, a member with both
the deacetylation and adenosine diphosphate (ADP)-ribosylation functions. The age-related
diseases are linked to the SIRT6 (Kitada, Kume et al. 2013). Sirt6 has been shown to be crucial
for the growth and survival in studies in mice. The severe progeria, or premature aging
condition, exhibited by the Sirt6 mouse which is the knockout in which the gene which is the
encode the Sirt6 has been destroyed, is marked by the spinal curvature, lymphopenia, and the
low blood glucose levels (Lombard, Schwer et al. 2008). The SIRT6 has a variety of functions
that control the aging, cell proliferation, metabolism, and the integrity of the genome. The
amount of the female follicles which is the site of developing oocyte as well as the size of eggs
are believed to gradually decline as the ovary ages. The quantity of primary follicles represents
ovarian reserve. The cytoplasm and nucleus of oocytes contain sirtuins, including the SIRT6,
which have been shown to inhibit the ovarian development (Luo, Chen et al. 2012).
Role of Sirtuin6 in Male Reproduction
Spermatogenesis: In the ending of the meiosis to the removal of the development or mature
male germ cells called spermatozoa, spermatid differentiation takes place during
spermiogenesis (Almeida, Rato et al. 2017). In meiosis, the diploid number of spermatocytes
which produces the four singled cells spermatids as compared to mitosis in which the number
of chromosomes is same as the parents and as a result identical individual are produced and if
some defective changes occur in the meiosis. Then the infertility occurs in the males, and they
do not produce the sperms. The formation of the acrosome, nuclear chromatin condensation,
mitochondrial rearrangement, association of the flagella of the male germ cell as well as
elimination of extra cytoplasm to promote sperm movement are among the structural changes
that occur in spermatids during this period (Liszt, Ford et al. 2005). Departure changes in the
structure as well as the working of the sperm come from the failures in any of these critical
processes (Calvel, Rolland et al. 2010). The Sirtuin6 may have a function in the preferences
because it is crucial to spermatogenesis. The Male fertility is the significantly impacted by the
ageing, and the elderly men show the noticeable reproductive disturbances. The morphological
and functional changes in the aging testis may have an impact on reduced hormone output,
including that of gonadotropin-releasing hormone, luteinizing hormone (LH),follicle
stimulating hormone (FSH), and testosterone. Since the Sirt6 deletion can increases the aging
in rodents, the SIRT6 may therefore offer protection against diseases linked to aging. Since
round to elongated spermatids express SIRT6, Sirt6 directly contributes to the growth of germ
cells.
Methodology
In that study first perform the immunostaining to determine the location of sirtuin6 in male
testis to investigate its function. In that study, make the two groups of mice. In the first group,
he kept those mice which have the knockout positive sirt6 and in the second group he kept
those mice which have negative knockout sirt6 and observed these two groups. Group first
which have the positive sirt6, in which the level of sirtuin6 is increased.so these mice were
survived and this sirtuin6 is expressed in the mice and these mice have the normal
spermatogenesis means round and elongated sperms which have the normal structural like
flagella which helps the sperm in the movement and the acrosomal head and normal function
while in the second group which have the negative or low level of sirtuin6 were died in 4 week
and sometimes after 8 week they die. In these mice the survival rate was low, and these mice
have the abnormal morphology of the sperms or spermatogenesis abnormal structure of
acrosomal head and flagella. In this way, we find out that the SIRT6 has the important role in
spermatogenesis (formation of sperms).
Conclusion
Sirtuin6 have the vital role in both male and female reproductive system. In
females it prevents from ovarian cancer and promote the oogenesis and prevent from premature
labor and role in the fertilization from the outside of the female body and prevent from the
cancer in the endometrium while in males sirtuin 6 promotes the spermatogenesis and
formation of normal sperms. If the level of sirtuin6 decreases in both male and female, then the
abnormal morphology occurs both in sperms and eggs. So, sirtuin6 may protect against ageassociated diseases. We can say that sirtuin6 is very important in both male and female
reproduction and it cure the age-related disease both in male and female.
Acknowledgement
I am very thankful to Dr. Usman Elahi and Department of biological sciences for encouraging
me to write this article.
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