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Chapter 4 Regulation of Gene Expression, Transcription, Splicing, and RNA Metabolism 39

HNF4α1 Factor IX gene
TATA box Exon Intron
Enhancer Promoter Enhancer

Transcription into factor IX mRNA

Translation into factor IX protein

A

Factor IX gene

Enhancer Promoter Enhancer
No transcription or translation

B Hemophilia B
Fig. 4.2 ROLE OF TRANSCRIPTION FACTOR BINDING SITES IN THE REGULATION OF
EUKARYOTIC GENE EXPRESSION. (A) Schematic diagram of a eukaryotic promoter showing transcrip-
tion factor binding sites in the promoter region before the factor IX gene, the TATA box, and the start site
of transcription (red ×). Not shown are histones, coregulators, mediators, or chromatin remodeling complexes.
(B) Effect of a mutation in the HNF4α1 binding site on expression of the blood coagulation gene factor IX.

Histones Repressor
CH3 complex CH3
DNA strand

CH3 CH3 CH3 CH3
A Nucleosome Target gene

mRNA
COCH3
COCH3
RNA COCH3 COCH3
DNA strand polymerase

COCH3 COCH3 COCH3 COCH3
B Target gene
Fig. 4.3 CHROMATIN STRUCTURE. (A) The nucleosome is the fundamental unit of chromatin and is
made up of DNA coiled around histone proteins. In a condensed state, the DNA is tightly wrapped around
histone complexes and target genes are inaccessible to transcription machinery. (B) Histones and DNA can
be epigenetically modified by acetylation and methylation, rendering the target genes more accessible to
transcription machinery.

Mutations in promoter sequences that result in decreased tran- factors affect the openness of chromatin, and therefore regulate avail-
scription factor binding, and therefore less RNA polymerase binding, ability of the DNA to transcription factors and RNA polymerases.
result in decreased gene expression. One of the best examples of a There are two types of chromatin: euchromatin and heterochromatin.
mutation in a transcription factor binding site associated with a Euchromatin refers to loosely packaged DNA, where RNA polymer-
human disease is in the factor IX gene. The transcription factor ases can freely bind to DNA and genes are actively transcribed.
HNF4α is required to bind to the factor IX promoter before this Heterochromatin refers to tightly packaged DNA, protected from
gene can be transcribed. Patients with a mutation in the HNF4α transcription machinery, sequestering genes away from transcription.
binding site can develop hemophilia B, an X-linked recessive bleeding The basic unit of chromatin is the nucleosome, which contains eight
disorder primarily affecting males (Fig. 4.2). histone proteins packaging 146 base pairs of DNA wound 1.7 times
The ability of transcription factors and RNA polymerases to access around the histone complex (Fig. 4.3).
specific promoters and transcribe genes is also regulated by the These histones can be extensively modified to regulate the acces-
packaging of DNA into discrete packets by proteins generically sibility of the DNA to the transcriptional apparatus. Histones can be
termed chromatin. Chromatin can package DNA tightly or loosely, chemically modified by acetylation, methylation, phosphorylation, or
and this regulates the availability of a gene for transcription. Several ubiquitination. In general, acetylation opens the nucleosome to