EPIGENETIC INFLUENCES

AND DISEASE
PROF BAGIADA
AAM TEAM
 EPIGENETIC
THE BEHAVIOR OF A PERSONS
GENES DOESNT JUST DEPEND ON
THE GENES DNA SEQUENCE
IT IS ALSO AFFECTED BY SO-CALLED
EPIGENETIC FACTORS.
CHANGES IN THESE FACTORS CAN
PLAY A CRITICAL ROLE IN DISEASE.
 WHAT IS EPIGENETIC
EPIGENETIC INVOLVE GENETIC
CONTROL BY FACTORS OTHER THAN
AN INDIVIDUALS DNA SEQUENCE
EPIGENETIC CHANGES CAN SWITCH
GENES ON OR OFF AND DETERMINE
WHICH PROTEIN ARE TRANSCRIBE
 HOW DO EPIGENETIC
CHANGES AFFECT GENES.
EPIGENETIC INVOLVES IN MANY NORMAL
CELLULAR PROCESSES
CONSIDER THE FACT THAT OUR CELLS ALL
HAVE THE SAME DNA, BUT OUR BODIES
CONTAIN MANY DIFFERENT TYPE OF CELLS
HOW CAN IT BE.
IN SORT, CELLS, TISSUE AND ORGAN
DIFFER BECAUSE THEY HAVE CERTAIN
SETS OF GENES, THAT ARE TURNED ON
OR EXPRESSED, AS WELL AS OTHER SETS
THAT ARE TURNED OFF OR INHIBITED
 EPIGENETIC SILENCING IS ONE WAY TO TURN GENES
OFF, AND CAN CONTRIBUTE TO DIFFERENCIAL
EXPRESSION.
SILENCING MIGHT ALSO EXPLAIN, IN PART, WHY
GENETIC TWIN ARE NOT PHENOTYPICALLY IDENTICAL
IN ADDITION EPIGENETIC IS IMPORTANT FOR X-
CHROMOSOME INACTIVATION IN FEMALE MAMMALS.
SO THAT FEMALES DONT HAVE TWICE THE NUMBER
OF X-CHROMOSOME GENE PRODUCTS AS MALE.
THUS THE SIGNIFICANS OF TURNING GENES OFF VIA
EPIGENETIC CHANGES IS READILY APPARENT
 THREE SYSTEMS THAT CAN
INTERACT EACH OTHER TO
SILENCE GENES
1. DNA METHYLATION

1. HISTONE MODIFICATION

2. RNA ASSOCIATED SILENCING

 DNA METHYLATION
IS CHEMICAL PROCESS THAT ADD A
METHYL GROUP TO DNA.
IT IS HIGHLY SPECIFIC AND ALWAYS HAPPEN
IN REGION IN WHICH A GUANOSINE
NUCLEOTIDE IS LOCATED NEXT TO A
SYTOSINE NUCLEOTIDE THAT IS LINK BY A
PHOSPHATE. THIS IS CALLED TO CpG SITE.
CpG SITE ARE METHYLATED BY ONE OF THE
THREE ENZYME CALLED DNA-
METHYLTRANSVERASES (DMNTs)
 DNA METHYLATION
CONT..
INSERTING METHYL CROUP CHANGES THE
APPE - ARANCE AND STRUCTURE OF DNA ,
MODIFYING A GENES INTERACTION WITH
THE MACHINERY WITHIN CELLS NUCLEUS
THAT IS NEED FOR TRANSCRIPTION
DNA METHYLATION IS USE IN SOME GENES
TO DIFFRENTIATE WHICH GENE COPY IS
INHERITED FROM THE FATHER AND WHICH
ONE IS FROM THE MOTHER, A
PHENOMENONE KNOWN AS IMPRINTING
 HISTON MODIFICATION
HISTONE ARE PROTEIN THAT ARE THE
PRIMARY COMPONENT OF CHROMATIN
HISTONE ACT AS SPOOL AROUND WHICH
DNA CAN WIND .
WHEN HISTON ARE MODIFIED AFTER THEY
ARE TRANSLATED INTO PROTEIN (POST
TRANSLATED MODIFICATION), THEY CAN
INFLUENCE HOW CHROMATIN IS ARRANGE,
WHICH IN TURN, CAN DETERMINED
WHETHER THE ASSOSIATED CHROMOSOMAL
DNA WILL BE TRANSCRIBED
 IF CHROMATIN IS CONDENSED
CREATING COMPLEX CALLED
HETEROCHROMATIN, THEN IT IS
INACTIVE AND DNA TRANSCRIPTION
DOES NOT OCCUR.
 TWO MAIN WAYS HISTONE
CAN BE MODIFIED
1. ACETYLATION
2. METHYLATION
THESE ARE CHEMICAL PROCESSES THAT
ADD EITHER AN ACETYL OR METHYL
GROUP RESPECTIVELY TO THE AMINO
ACID LYSINE THAT IS LOCATED IN
HISTONE.
ACETYLATION IS USUALLY ASSOCIATED
WITH ACTIVE CHROMATIN, WHILE
DEACETYLATION IS GENERALLY
ASSOCIATED WITH HETEROCHROMATIN.
 ON THE OTHER HAND HISTONE
METHYLATION CAN BE A MARKER FOR
BOTH ACTIVE AND IN ACTIVE REGIONS OF
CHROMATIN. FOR EXAMPLE METHYLATION
OF PARTICULAR LYSINE (K9) ON SPESIFIC
HISTONE (H3) THAT MARKED SILENT DNA
IS WIDELY DISTRIBUTE INACTIVATED
THROUGH HETEROCHROMATIN.
THIS IS THE TYPE OF EPIGENETIC CHANGE
THAT IS RESPONSIBLE FOR INACTIVATED
X-CHROM OF FEMALE
 IN CONTRAST METHYLATION OF
DIFFERENT LYCINE (K4) ON THE SAME
HISTON (H3) IS A MARKER FOR
ACTIVE GENES (EGGER ET AL.,2004)
 RNA ASSOCIATED
SILENCING
GENES CAN ALSO BE TURNED OFF BY
RNA WHEN IT IS IN THE FORM OF
ANTISENSE TRANSCRIPTS, NON CODING
RNA, OR RNA INTERFERENCE (RNAi)
RNA MIGHT AFFECT GENE EXPRESSION
BY CAUSING HETEROCHROMATIN TO
FORM OR BY TRIGERING HISTON
MODIFICATION AND DNA
METHYLATION.
 EPIGENETIC AND DISEASE
WHILE EPIGENETIC CHANGES ARE
REQUIRED FOR NORMAL DEVELOPMENT
AND HEALTH, THEY CAN ALSO BE
RESPONSBLE FOR SOME DISEASE STATES.
DISRUPTING ANY OF THE THREE SYSTEMS
THAT CONTRIBUTE TO EPIGENETIC
ALTERATION CAN CAUSE ABNORMAL
ACTIVATION OR SILENCING OF GENES
SUCH DISRUPTION HAS BEEN ASSOCIATED
WITH CANCER, SINDROME INCLUDING
CHROMOSOMAL INSTABILITIES AND
MENTAL RETARDATION
 EPIGENETIC AND CANCER
THE FIRST HUMAN DISEASE TO BE LINKED TO
EPIGENETIC WAS CANCER (1983).
REASEARCHES FOUND THAT DISEASED TISSUE
OF COLORECTAL CANCER HAD LESS DNA
METHYLATION THAN NORMAL TISSUE FROM
THE SAME PATIENT (FEINBERG & VOGELSTEIN
1983)
BECAUSE METHYLATED GENES ARE TYPICALLY
TURNED OFF, LOSS OF DNA METHYLATION CAN
CAUSE ABNORMALLY HIGH GENE ACTIVATION
BY ALLERING THE ARRANGEMENT OF
CHROMATIN
 ON THE OTHER HAND TOO MUCH
METHYLATION CAN UNDO THE WORK OF
PROTECTIVE TUMOR SUPRESSOR GENE.
AS PREVIOUSLY MENTIONED DNA
METHYLATION OCCUR IN CpG SITES AND
A MAJORITY OF CpG CYTOSINES ARE
METHYLATED IN MAMMALS.
HOWEVER THERE ARE STRETCHES OF DNA
NEAR PROMOTER REGION THAT HAVE
HIGHER CONCENTRATION OF CpG SITES
(KNOWN AS CpG ISLAND) THAT ARE FREE
FROM METHYLATION IN NORMAL CELLS .
 THESE CpG ISLAND BECOME EXESIVELY
METHYLATED IN CANCER CELLS
THEREBY CAUSING GENES THAT
SHOULD NOT BE SILENCED TO TURN OFF
THIS ABNORMALLY IS THE TRADEMARK
EPIGENETIC CHANGE THAT OCCUR IN
TUMOR AND HAPPEN EARLY IN
DEVELOPM ENT OF CANCER
HYPERMETHYLATION OF CpG ISLAND
CAN CAUSE TUMORS BY SHUTTING OFF
TUMOR SUPPRESOR GENE
 Furthemore, although epigenetic changes do not
alter the sequence of DNA, they can cause
mutations.
About half of genes that cause familial on
inherited forms of cancer are turned off by
methylation. Most of these genes normally
suppress tumor formation and help repair DNA,
including O6 methylguanine-
DNAmethyltransferse (MGMT), MLH1 cyclin-
dependent kinase inhibitor 2B (CDKN28), and
RASSF1A. For example, hypermethylation of the
promoter of MGMT causes the number of G-to-A
mutations to increase (figure 2).
 Hypermethylation can also lead to instability of
microsatellites, which are repeated sequences of
DNA.
Microsatellites are common in normal individuals,
and they usually consist of repeats of the
dinucleotide CA.
Too much methylation of the promoter of the DNA
repair gene MLH1 can make a microsatellite
unstable and lengthen or shorten it (Figure 2).
Microsatellite instability has been linked to many
cancers, including colorectal, endometrial, ovarian,
and gastric cancers (Jones & Baylin, 2002).
 EPIGENETIC AND MENTAL
RETARDATION
FRAGILE X-SYNDROME ARE THE MOST FREQUENTLY
INHERITED MENTAL DISABILITY PARTICULARY IN MALE.
BOTH SEXES CAN BE AFFECTED BY THIS CONDITION
BECAUSE MALES ONLY HAVE ONE X-CHROMOSOME
ONE FRAGILE X WILL IMPACT THEM SEVERELY
INDEED ITS OCCUR 1: 4000 MALES AND 1:
8000 IN FEMALE
PEOPLE WITH FRAGILE X SYNDROME HAVE
SEVERE INTELECTUAL DISABILITY, DELAYED
VERBAL DEVELOPMENT, AND AUTISTIC LIKE
BEHAVIOR
 FRAGILE X-SYNDROME GETS ITS NAME FROM THE WAY
THE PART OF THE X CHROMOSOME THAT CONTAIN THE
GEN ABNORMALY LOOK UNDER THE MICROSCOPE.
EASILY BREAKABLE
SYNDROME CAUSE BY AN ABNORMALY IN THE FMR1
(FRAGILE X MENTAL RETARDATON 1) GENE
PEOPLE WHO DO NOT HAVE FRAGILE X SYNDROME
HAVE 6 TO 50 REPEATS OF THE 3 NUCLEOTIDE CGG IN
THEIR FMR1 GENE
INDIVIDUAL WITH OVER THAN 200 REPEATS WILL
SHOW SYMPTOM OF THE SYNDROME
TOO MANY CGGs CAUSE THE CpG OF FMR1 GENE TO
BECOME METHYLATED, NORMALY THEY ARE NOT
THIS METHYLATION TURNS THE GENE OFF STOP
PRODUCTION OF IMPORTANT PROTEIN CALLED
FRAGILE X MENTAL RETARDATON PROTEIN
 COMBATING DISEASES WITH
EPIGENETIC THERAPY
INHIBITOR OF DNA METHYLATIONS CAN
REACTIVATE GENES THAT HAVE BEEN
SILENCED
TWO EXAMPLE TYPES OF THESE DRUGS :
5-AZACYTIDINE AND 5-AZA 2-DEOXY CYTIDINE
WORK BY ACTING LIKE THE NUCLEOTIDA
CYTOSIN AND INCOMPORATING THEMSELVES
INTO DNA WHILE IT IS REPLICATING
AFTER THEY ARE INCORPORATED INTO DNA,
THE DRUGS BLOCK DNMP ENZYME FROM
ACTING WHICH INHIBIT DNA METHYLATION.