WEBVTT

00:00:01.611 --> 00:00:03.861
So, the regulation of
gene expression can be

00:00:03.861 --> 00:00:06.969
modulated at virtually any
step in the process, from

00:00:06.969 --> 00:00:10.377
the initiation of
transcription all the way to

00:00:10.377 --> 00:00:13.078
post-translational
modification of a protein,

00:00:13.078 --> 00:00:15.895
and every step in between.

00:00:15.895 --> 00:00:19.454
And it's the ability to regulate
all these different steps

00:00:19.454 --> 00:00:21.604
that helps the cell to have

00:00:21.604 --> 00:00:25.078
the versatility and the adaptability of

00:00:25.078 --> 00:00:28.429
an efficient ninja, so
that it expends energy to

00:00:28.429 --> 00:00:31.581
express the appropriate
proteins only when needed.

00:00:31.581 --> 00:00:33.612
Or, you can think of the cell as

00:00:33.612 --> 00:00:35.395
a lazy couch potato that wants to expend

00:00:35.395 --> 00:00:37.877
the least amount of energy as possible.

00:00:37.877 --> 00:00:40.304
So, starting at the
beginning of gene expression,

00:00:40.304 --> 00:00:42.512
let's talk about gene regulation

00:00:42.512 --> 00:00:47.105
as it pertains to DNA
and chromatin regulation.

00:00:47.536 --> 00:00:49.611
Let's talk about the structure of DNA.

00:00:49.611 --> 00:00:52.742
DNA is packed into
chromosomes in the form of

00:00:52.742 --> 00:00:57.596
chromatin, also know as supercoiled DNA.

00:00:57.596 --> 00:01:00.395
And so, chromatin is made up of DNA,

00:01:00.395 --> 00:01:03.835
histone proteins, and
non-histone proteins.

00:01:03.835 --> 00:01:06.504
And there are repeating
units in chromatin,

00:01:06.504 --> 00:01:09.844
called nucleosomes, which are made up of

00:01:09.844 --> 00:01:14.661
146 base pairs of double
helical DNA that is

00:01:14.661 --> 00:01:18.827
wrapped around a core of eight histones.

00:01:18.827 --> 00:01:21.753
And there are four different
types of histones within

00:01:21.753 --> 00:01:25.170
this structure of eight
that you should be aware of.

00:01:25.170 --> 00:01:31.545
And they're named H2A, H2B, H3, and H4,

00:01:31.545 --> 00:01:34.012
that's just the nomenclature
they've been given.

00:01:34.012 --> 00:01:37.969
Now, acetylation occurs at
the amino terminal tails

00:01:37.969 --> 00:01:40.961
of these histone proteins
by an enzyme called

00:01:40.961 --> 00:01:43.174
histone acetyltransferase,

00:01:43.174 --> 00:01:46.495
which I'll just abbreviate as HAT.

00:01:46.495 --> 00:01:49.754
And this is a reversible
modification, so the

00:01:49.754 --> 00:01:52.836
acetylation of histones
is sort of kept in balance

00:01:52.836 --> 00:01:56.128
by another enzyme that
removes these acetyl groups,

00:01:56.128 --> 00:02:01.690
which is called histone
deacetylase, or HDAC.

00:02:01.690 --> 00:02:04.611
The acetylation of histones leads to

00:02:04.611 --> 00:02:07.739
uncoiling of this chromatin
structure, and this

00:02:07.739 --> 00:02:10.928
allows it be accessed by
transcriptional machinery

00:02:10.928 --> 00:02:13.345
for the expression of genes.

00:02:13.345 --> 00:02:17.309
On the flip side of this,
histone deacetylation leads to

00:02:17.309 --> 00:02:20.544
a condensed, or closed
structure of the chromatin,

00:02:20.544 --> 00:02:23.262
and less transcription of those genes.

00:02:23.262 --> 00:02:25.015
When these modifications that regulate

00:02:25.015 --> 00:02:27.077
gene expression are inheritable,

00:02:27.077 --> 00:02:30.900
they are referred to as
epigenetic regulation.

00:02:30.900 --> 00:02:33.656
So, when it comes to
gene expression and DNA,

00:02:33.656 --> 00:02:35.388
you can basically think of DNA

00:02:35.388 --> 00:02:37.983
as coming in two flavors,

00:02:37.983 --> 00:02:41.994
densely packed, and
transcriptionally inactive DNA,

00:02:41.994 --> 00:02:45.327
which is called heterochromatin,
and then less dense,

00:02:45.327 --> 00:02:49.637
transcriptionally active
DNA, which is euchromatin.

00:02:49.637 --> 00:02:52.228
And I like to think of
heterochromatin as being

00:02:52.228 --> 00:02:56.062
densely packed and hibernating,
like heterochromatin

00:02:56.062 --> 00:02:58.978
and hibernating both begin
with H, kind of like a

00:02:58.978 --> 00:03:00.595
bunch of densely packed bears that are

00:03:00.595 --> 00:03:02.716
closed off in their cave for the winter,

00:03:02.716 --> 00:03:04.661
whereas euchromatin is waiting there

00:03:04.661 --> 00:03:06.128
with open arms, welcoming the

00:03:06.128 --> 00:03:09.428
transcriptional machinery
to transcribe away.

00:03:09.428 --> 00:03:12.817
Now often you will see
that histone deacetylation

00:03:12.817 --> 00:03:16.145
is combined with another type of

00:03:16.145 --> 00:03:18.038
DNA regulatory mechanism,

00:03:18.038 --> 00:03:20.533
and that is DNA methylation, and

00:03:20.533 --> 00:03:24.645
this occurs in a process
called gene silencing.

00:03:24.645 --> 00:03:27.428
And this is a more
permanent method of sort of

00:03:27.428 --> 00:03:30.512
down-regulating the
transcription of genes.

00:03:30.512 --> 00:03:32.953
And DNA methylation
involves the addition of a

00:03:32.953 --> 00:03:36.695
methyl group, which is a
carbon with three hydrogens,

00:03:36.695 --> 00:03:39.928
to the cytosine, DNA nucleotides,

00:03:39.928 --> 00:03:44.544
by an enzyme appropriately
called methyltransferase.

00:03:44.544 --> 00:03:46.027
And this typically occurs in

00:03:46.027 --> 00:03:49.991
cytosine-rich sequences
called CpG islands.

00:03:49.991 --> 00:03:53.428
Don't forget that cytosine
pairs with g, guanine,

00:03:53.428 --> 00:03:56.512
so that's why they're cg
islands that you'll find.

00:03:56.512 --> 00:03:58.534
DNA methylation stably alters

00:03:58.534 --> 00:04:00.355
the expression of genes, and so

00:04:00.355 --> 00:04:03.178
it occurs as cells
divide and differentiate

00:04:03.178 --> 00:04:07.544
from embryonic stem cells
into specific tissues.

00:04:07.544 --> 00:04:10.661
And so this is essential
for normal development,

00:04:10.661 --> 00:04:13.911
and is associated with
other processes, such as

00:04:13.911 --> 00:04:17.395
genomic imprinting, and
x-chromosome inactivation,

00:04:17.395 --> 00:04:19.428
topics for another discussion.

00:04:19.428 --> 00:04:21.712
And abnormal DNA methylation has been

00:04:21.712 --> 00:04:25.077
implicated in carcinogenesis, or the

00:04:25.077 --> 00:04:28.044
development of cancer,
so you can see how the

00:04:28.044 --> 00:04:30.968
normal functioning of DNA methylation is

00:04:30.968 --> 00:04:35.691
a critical regulatory
mechanism for our cells.

00:04:36.062 --> 00:04:37.848
Now, DNA methylation may effect

00:04:37.848 --> 00:04:40.461
the transcription of genes in two ways.

00:04:40.461 --> 00:04:42.646
First, the methylation of DNA itself

00:04:42.646 --> 00:04:44.524
may physically impede the binding

00:04:44.524 --> 00:04:47.895
of transcriptional proteins to the gene.

00:04:47.895 --> 00:04:50.552
And second, and likely more important,

00:04:50.552 --> 00:04:53.794
methylated DNA may be
bound by proteins known as

00:04:53.794 --> 00:04:56.513
methyl cpg-binding domain proteins,

00:04:56.513 --> 00:04:59.032
or MBDs, for short.

00:04:59.032 --> 00:05:01.952
Now MBD proteins can then
recruit additional proteins

00:05:01.952 --> 00:05:05.589
to the locus, or particular
location in a chromosome,

00:05:05.589 --> 00:05:08.689
certain genes, such as
histone deacetylases,

00:05:08.689 --> 00:05:11.189
and other chromatin
remodeling proteins, and this

00:05:11.189 --> 00:05:14.203
modifies the histones, forming condensed,

00:05:14.203 --> 00:05:17.178
inactive heterochromatin that is

00:05:17.178 --> 00:05:20.203
basically transcriptionally silent.