Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia.
We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.
Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Spain.
Marta
M
Kulis
Simon
S
Heath
Marina
M
Bibikova
Ana C
AC
Queirós
Alba
A
Navarro
Guillem
G
Clot
Alejandra
A
Martínez-Trillos
Giancarlo
G
Castellano
Isabelle
I
Brun-Heath
Magda
M
Pinyol
Sergio
S
Barberán-Soler
Panagiotis
P
Papasaikas
Pedro
P
Jares
Sílvia
S
Beà
Daniel
D
Rico
Simone
S
Ecker
Miriam
M
Rubio
Romina
R
Royo
Vincent
V
Ho
Brandy
B
Klotzle
Lluis
L
Hernández
Laura
L
Conde
Mónica
M
López-Guerra
Dolors
D
Colomer
Neus
N
Villamor
Marta
M
Aymerich
María
M
Rozman
Mónica
M
Bayes
Marta
M
Gut
Josep L
JL
Gelpí
Modesto
M
Orozco
Jian-Bing
JB
Fan
Víctor
V
Quesada
Xose S
XS
Puente
David G
DG
Pisano
Alfonso
A
Valencia
Armando
A
López-Guillermo
Ivo
I
Gut
Carlos
C
López-Otín
Elías
E
Campo
José I
JI
Martín-Subero
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D001402:B-Lymphocytes / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged